Inhibitors of protein methyltransferase dot1l and methods of use thereof

ABSTRACT

The present invention relates to DOT1L inhibitors and methods of identifying, designing, or optimizing them. The present invention also relates to crystals of DOT1L-inhibitor complexes, the crystal structures thereof, and the use of the crystal structures. Also disclosed are pharmaceutical compositions containing these DOT1L inhibitors and methods of treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer and neurological disorders, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S. Provisional Application No. 61/682,090, filed Aug. 10, 2012, the entire content of which is incorporated herein in its entirety.

SUMMARY OF THE INVENTION

The invention is based upon the discovery that a surprising conformational adaptation results in high-affinity inhibitor binding of aminonucleoside inhibitors of DOT1L to the enzyme and prolonged residence time.

The invention provides compounds useful for selectively inhibiting DOT1L. The present invention also provides pharmaceutically acceptable salts, esters, and/or N-oxides, of these compounds.

The invention further features a method for designing, identifying, and/or optimizing a candidate DOT1L inhibitor.

In one aspect, the invention features a compound of Formula (I) below or a pharmaceutically acceptable salt or ester thereof:

wherein,

Nuc is adenosine-like moiety or an analog or a derivative thereof,

T is a linker group of a 6-10 carbon atoms, in which one or more carbon atoms are optionally replaced with a heteroatom and T is optionally substituted;

Nuc-T is capable of binding within the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO: 1; and

R₉ is a group such that R₉ induces a conformational adaptation in human DOT1L, wherein the conformational adaptation is the formation of a hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO: 1; and

further wherein Nuc-T is capable of binding within the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO: 1.

In another aspect, the invention features a method for designing and/or identifying a potential binding compound for protein DOT1L. The method comprises:

(a) generating, on a computer, a three-dimensional structure of DOT1L having the structural coordinates of Table S1 or S2;

-   -   (b) identifying amino acid residues forming an hydrophobic         pocket site in the three-dimensional structure of DOT1L from         step (a), wherein the hydrophobic pocket domain of DOT1L is         characterized by the crystallography coordinates of human DOT1L         amino acids Leu143, Met147, Phe239, and Tyr312 according to         Table S1 or S2;

(c) generating a three-dimensional model of the active site;

(d) designing and/or selecting a compound that potentially binds to the active site using the three-dimensional model of the active site; and

(e) synthesizing and/or choosing the potential binding compound.

In yet another aspect, the invention features a method for designing and/or identifying a potential binding compound for protein DOT1L, the method comprising computationally identifying a binding compound that binds to DOT1L using the atomic coordinates of Leu143, Met147, Phe239, and Tyr312 according to Table S1 or S2.

In still another aspect, the invention features a method for designing and/or identifying a potential binding compound for protein DOT1L, the method comprising:

a) providing a set of atomic coordinates for human DOT1L as set forth in Table S1 or S2; and

-   -   b) identifying in silico a binding compound that binds to DOT1L         using the coordinates of step (a).

The invention also features a method of identifying a drug candidate for the treatment of a disease, the method comprising:

a) using the atomic coordinates set forth in Table S1 or S2 to form a three-dimensional structure of DOT1L;

b) selecting a test compound having the best fit with the structure of DOT1L; and

c) assaying the ability of the test compound to modulate DOT1L activity, wherein a test compound that modulates DOT1L activity is considered a drug candidate for treating a disease.

In another aspect, the invention features a DOT1L inhibitor having molecular dimensions compatible with the shape of a hydrophobic pocket domain of DOT1L characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr312, according to Table S1 or S2, wherein the compound has a biochemical IC₅₀ for DOT1L of less than 100 nM.

The invention also features a computer readable medium comprising the atomic coordinates of one or more DOT1L-Compound A2, DOT1L-Compound C1, DOT1L-Compound C118 and DOT1L-Compound D16.

The invention also features a method for designing, identifying, and/or optimizing a candidate DOT1L inhibitor compound or complex. The method comprises:

(a) generating a crystal structure, a three-dimensional model of DOT1L, or obtaining the structure coordinates of DOT1L in complex with the candidate DOT1L inhibitor compound or complex, and

(b) determining if the candidate DOT1L inhibitor compound or complex induces a conformational adaptation and/or a hydrophobic binding site of the DOT1L from the three-dimensional model.

In yet another aspect, the invention features a method for designing, identifying, and/or optimizing a candidate DOT1L inhibitor compound or complex that interacts with all or a part of a hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO: 1 and the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO: 1. The method includes

(a) producing the structure coordinates of the hydrophobic binding pocket of DOT1L in silico comprising the means for generating three-dimensional structural information from the coordinates;

(b) designing, selecting and/or optimizing the candidate DOT1L inhibitor compound or complex by performing a fitting operation between the candidate DOT1L inhibitor compound or complex and the three-dimensional structural information of all or part of the hydrophobic binding pocket or DOT1L protein; and

(c) optionally employing computerized and/or reiterative steps.

The invention also relates to a pharmaceutical composition of a compound of Formula (I) and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition comprising a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition of a salt of a compound of Formula (I) or a salt of a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition of a hydrate of a compound of Formula (I) or a hydrate of a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein and a pharmaceutically acceptable carrier.

The present invention provides methods of treating or preventing cancer. The present invention provides methods of treating cancer. The present invention also provides methods of preventing cancer. The method includes administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I) or a therapeutically effective amount of a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein. The cancer can be a hematological cancer. Preferably, the cancer is leukemia. More preferably, the cancer is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.

The present invention provides methods of treating or preventing a disease or disorder mediated by translocation of a gene on chromosome 11q23. The present invention provides methods of treating a disease or disorder mediated by translocation of a gene on chromosome 11q23. The present invention also provides methods of preventing a disease or disorder mediated by translocation of a gene on chromosome 11q23. The method includes administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I) or a therapeutically effective amount of a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein.

The present invention provides methods of treating or preventing a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The present invention provides methods of treating a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT-mediated protein methylation. The present invention also provides methods of preventing a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The method includes administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I) or a therapeutically effective amount of a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein.

The present invention provides methods of inhibiting DOT1L activity in a cell. The method includes contacting the cell with an effective amount of one or more of the compound of Formula (I) or one or more of the DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein.

Still another aspect of the invention relates to a method of reducing the level of Histone H3 Lysine residue 79 (H3-K79) methylation in a cell. The method includes contacting a cell with a compound of the present invention. Such method can be used to ameliorate any condition which is caused by or potentiated by the activity of DOT1 through H3-K79 methylation.

The present invention relates to use of the compounds disclosed herein in preparation of a medicament for treating or preventing cancer. The use includes a compound of Formula (I) for administration to a subject in need thereof in a therapeutically effective amount. The cancer can be a hematological cancer. Preferably, the cancer is leukemia. More preferably, the cancer is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.

The present invention provides use of the compounds disclosed herein in preparation of a medicament for treating or preventing a disease or disorder mediated by translocation of a gene on chromosome 11q23. The use includes a compound of Formula (I) or a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein for administration to a subject in need thereof in a therapeutically effective amount.

The present invention provides use of the compounds disclosed herein in preparation of a medicament for treating or preventing a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The use includes a compound of Formula (I) or a DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein for administration to a subject in need thereof in a therapeutically effective amount.

The present invention provides use of the compounds disclosed herein for inhibiting DOT1L activity in a cell. The use includes contacting the cell with an effective amount of one or more of the compound of Formula (I) and/or the DOT1L inhibitor designed, identified, and/or optimized by the method disclosed herein.

Still another aspect of the invention relates to a use of the compounds disclosed herein for reducing the level of Histone H3 Lysine residue 79 (H3-K79) methylation in a cell. The use includes contacting a cell with a compound of the present invention. Such use can ameliorate any condition which is caused by or potentiated by the activity of DOT1 through H3-K79 methylation.

In the formulae presented herein, the variables can be selected from the respective groups of chemical moieties later defined in the detailed description.

In addition, the invention provides methods of synthesizing the foregoing compounds. Following synthesis, a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use in modulating an epigenetic enzyme. In certain embodiments, the compounds of the present invention are useful for treating, preventing, or reducing the risk of cancer or for the manufacture of a medicament for treating, preventing, or reducing the risk of cancer. Accordingly, the compounds or the formulations can be administered, for example, via oral, parenteral, otic, ophthalmic, nasal, or topical routes, to provide an effective amount of the compound to the mammal.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DESCRIPTION OF THE FIGURES

FIG. 1 is a plot showing that Compound A2 causes complete and sustained tumor regression in a MV4-11 nude rat xenograft model of MLL-rearranged leukemia.

FIG. 2 includes plots showing biochemical characterization of Compound D16 inhibition of DOT1L. (A) Compound D16 is a competitive inhibitor with respect to SAM. The IC₅₀ of Compound D16 was determined as a function of SAM concentration relative to the K_(m) of SAM ([SAM]/K_(m)) and found to display a linear relationship as expected for competitive inhibition. Inset: Michaelis-Menten plot of product formation as a function of SAM concentration at various concentrations of Compound D16. The data were fit globally to a general equation for enzyme inhibition (Copeland R A, Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. New York: Wiley; 2005) and yield values of alpha of 10±6 and K_(i) of 0.3±0.03 nM. (B) Compound D16 is a noncompetitive inhibitor with respect to oligonucleosome (Nucl). The IC₅₀ of Compound D16 was determined as a function of Nuc concentration relative to the K_(m) of Nucl ([Nucl]/K_(m)) and found to be independent of [Nucl]/K_(m), as expected for noncompetitive inhibition. Inset: Michaelis-Menten plot of product formation as a function of Nuc concentration at various concentrations of Compound D16. The data were fit globally to a general equation for enzyme inhibition (Copeland, 2005) and yield values of alpha of 0.5±0.2 and K_(i) of 0.3±0.02 nM.

FIG. 3 is a plot showing superposition of SAM and Compound C1 within the active site of DOT1L, demonstrating conservation of binding motif. DOT1L-SAM co-crystal structure (PDB code: 3QOW): in line presentation (carbon atoms: light blue; oxygen: red; nitrogen: dark blue). SAM: stick presentation (carbon atoms: light blue; oxygen: red; nitrogen: dark blue, sulfur: yellow). Compound C1: stick presentation (carbon atoms: maroon; oxygen: red; nitrogen: dark blue). Hydrogen bonds between SAM and DOT1L are labeled by dashed lines.

FIG. 4A shows key contacts between DOT1L protein and the urea moiety of Compound C118 in the DOT1L-Compound C118 co-crystal structure. SAM is superimposed on to Compound C118. The interactions for 5′-amino and urea of Compound C118 are labeled by dashed lines. DOT1L protein of the DOT1L-Compound C118 co-crystal structure: in line presentation (carbon atoms: green; oxygen: red; nitrogen: dark blue). Compound C118: stick presentation (carbon atoms: green). SAM: stick presentation (carbon atoms: light blue)

FIG. 4B shows opening of the hydrophobic pocket within the DOT1L-Compound C118 co-crystal structure. Superimposition of DOT1L-SAM and DOT1L-Compound C118 demonstrates the opening of the hydrophobic pocket by the tert-butyl phenyl group on Compound C118. DOT1L structures are presented in Ca trace. The key residue side chains which open the pocket are displayed as in line presentation. Comparison of these residues in the DOT1L-SAM and DOT1L-Compound C118 structures shows the conformational change and resultant opening of the hydrophobic pocket upon the binding of Compound C118. DOT1L protein: in line presentation (carbon atoms: green for the DOT1L-Compound C118 structure and light blue for the DOT1L-SAM structure; oxygen: red; nitrogen: dark blue). Compound C118: stick presentation (carbon atoms: green). SAM: stick presentation (carbon atoms: light blue)

FIG. 4C shows loop disorder induced by binding of Compound C118 to DOT1L. Superimposition of DOT1L-SAM and DOT1L-Compound C118 shows the disorder in 130s' and 300s' loops upon the binding of Compound C118. DOT1L protein: in line presentation (carbon atoms: green for the DOT1L-Compound C118 structure and light blue for the DOT1L-SAM structure). Compound C118: stick presentation (carbon atoms: green; oxygen: red; nitrogen: dark blue). SAM: stick presentation (carbon atoms: light blue; oxygen: red; nitrogen: dark blue; sulfur: yellow)

FIG. 5 is superimposition of Compound D16 and Compound C118 structures. The DOT1L protein of DOT1L-Compound D16 is in surface presentation in grey. Compound D16 (carbon atoms: magenta) is superimposed with Compound C118 (carbon atoms: green).

FIG. 6 is a ligand plot to show the binding pockets of DOT1L in complex with Compound A2.

FIG. 7 is a ligand plot to show the binding pockets of DOT1L in complex with Compound D16.

FIG. 8 is a ligand plot to show the binding pockets of DOT1L in complex with Compound D8.

FIG. 9 is a ligand plot to show the binding pockets of DOT1L in complex with Compound C118.

FIG. 10 is a series of images showing 2Fo-Fc maps for Compounds C1 (A), C118 (B) and D16 (C). All maps were contoured at 1 σ.

DETAILED DESCRIPTION OF THE INVENTION

Certain aspects of the present invention provide compounds that can be used to selectively modulate the aberrant action of an epigenetic enzyme. Further, the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by aberrant action of an epigenetic enzyme. The present invention includes pharmaceutically acceptable salts, esters, tautomers, and N-oxides of these compounds. Certain aspects of the present invention also provide methods of designing, identifying, and/or optimizing novel compounds as DOT1L inhibitors, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the compounds.

One aspect of the present invention relates to compounds that selectively modulate the activity of the histone methyltransferase DOT1L, an enzyme known to methylate lysine 79 of histone H3 (“H3K79”) in vivo (Feng et al. (2002) Curr. Biol. 12:1052-1058). Similar to other HMTases, DOT1L contains a S-adenosylmethionine (SAM) binding site and uses SAM as a methyl donor. However, unlike other reported HMTases, the DOT1 polypeptides do not contain a SET domain.

DOT1L nucleic acid and polypeptides have previously been described (see, e.g., U.S. Patent Application Publication No. 2005-0048634 A1 (hereby incorporated by reference); Feng et al. (2002) Curr. Biol. 12:1052-1058; and Okada et al. (2005) Cell 121:167-78). The sequences of the human nucleic acid and protein have been deposited under GenBank Accession No. AF509504, which is hereby incorporated by reference in its entirety. Only the approximately 360 N-terminal amino acids of hDOT1L share significant sequence similarity with the yeast DOT1. In addition, DOT1 homologs from C. elegans (GenBank Accession Nos. NP510056 and CAA90610), Drosophila (GenBank Accession Nos. CG10272 and AAF54122), mouse (GenBank Accession No. XP125730), Anopheles gambiae (GenBank Accession No. EAA03558), and Neurospora crassa (GenBank Accession No. EAA33634) are available in public databases (the disclosures of which are incorporated by reference herein in their entireties). The SAM binding domain among these homologs is conserved (approximately 30-100% amino acid sequence identity and 50-100% amino acid similarity). Various aspects of the present invention can be practiced with any DOT1L polypeptide or nucleic acid.

The 2.5 angstrom resolution structure of a fragment of the hDOT1L protein containing the catalytic domain (amino acids 1-416; SEQ ID NO: 1) has been solved, and the atomic coordinates for amino acids 1-416 of hDOT1L have been determined and deposited in the RCSB database under ID code 1NW3 and described in the scientific literature (Min et al. (2003) Cell 112:711-723), the disclosures of both of which are incorporated herein by reference in their entireties. As an example, human DOT1L includes the protein comprising SEQ ID NO: 1 and variants thereof comprising at least about 70% amino acid sequence identity to SEQ ID NO: 1, or preferably 80%, 85%, 90% and 95% sequence identity to SEQ ID NO:1, or more preferably, at least about 95% or more sequence identity to SEQ ID NO:1.

It has recently been demonstrated that hDOT1L plays an important role in MLL-AF10-mediated leukemogenesis (Okada et al. (2005) Cell 121:167-78). It was also shown that mistargeting of hDOT1L to the Hoxa9 gene by MLL-AF10 results in H3K79 methylation and Hoxa9 upregulation which contributes to leukemic transformation (Okada et al. (2005) Cell 121:167-78). It was further demonstrated that the hDOT1L and MLL-AF10 interaction involves the OM-LZ (octapeptide motif-leucine zipper) region of AF10, required for MLL-AF10-mediated leukemic transformation (DiMartino et al. (2002) Blood 99:3780-5). It has also been shown that CALM-AF10 fusion appears to be both necessary and sufficient to mediate leukemogenesis in vitro and in vivo; that hDOT1L and its H3K79 methyltransferase activity are implicated in CALM-AF10-mediated leukemic transformation; and that the Hoxa5 gene is involved in CALM-AF10-mediated transformation (U.S. Patent Application Publication No. 2009-0061443 A1, which is hereby incorporated by reference in its entirety). Aberrant recruitment of DOT1L leading to deregulated gene expression may be a common feature of many other oncogenic MLL-fusion proteins. For example, the MLL fusion partners ENL, AF4, and AF9 are normally found in nuclear complexes with DOT1L (Bitoun et al. (2007) Hum. Mol. Genet. 16:92-106, Mueller et al. (2007) Blood 110:4445-54, Zhang et al. (2006) J. Biol. Chem. 281:18059-68), and altered H3K79 methylation profiles are a feature of murine and human MLL-AF4 leukemias (Krivstov et al. (2008) Cancer Cell 14:355-368).

The present disclosure presents the design and optimization of a series of aminonucleoside inhibitors of the PKMT DOT1L. Using the crystal structures of various aminonucleoside inhibitors bound to human DOT1L, the key recognition elements of ligand binding to the enzymatic active site have been systematically defined. Conformational adaptation is a common feature of enzyme catalysis and of high-affinity ligand interactions with enzymes. This is clearly the case with the potent aminonucleoside inhibitors of DOT1L. A novel hydrophobic pocket, immediately adjacent to the SAM binding site of the enzyme has been discovered by the applicants. It was opened up to accommodate the extended aminonucleoside compounds that had been originally designed to engage the lysine binding channel of the contiguous enzyme active site. This structural adaptation results in very high-affinity binding of aminonucleosides to the enzyme and provided new directions for inhibitor optimization. The conformational adaptation mechanism of inhibitor binding demonstrated for the aminonucleosides also results in extended residence time for the optimized members of this inhibitor series. For example, D16 displays a DOT1L enzyme residence time of sixty minutes, as measured by surface plasmon resonance. A long residence time on PMT targets, such as DOT1L, may prove to be of value in demonstrating durable pharmacology in patients.

The invention features a method of designing, identifying, and/or optimizing an inhibitor of DOT1L, e.g., an aminonucleoside DOT1L inhibitor. The designing of inhibitors can be initiated using mechanism-guided design principles, based on the DOT1L enzymatic reaction mechanism, and optimized through structure-guided approaches using iterative enzyme-inhibitor complex crystal structures. In embodiments, conformational adaptation of the enzyme active site attends potent inhibitor binding and this observation can be taken into account to develop a cogent structure-activity relationship (SAR) for active site-directed DOT1L inhibition. In one embodiment, this optimization process results in Compound D16, which is a picomolar inhibitor of DOT1L with exquisite selectivity for its target enzyme. Compound D16 has been shown to demonstrate potent and selective killing of MLL-rearranged leukemic cells, both in cell culture and in a highly aggressive disseminated mouse model of this disease. Thus, the methods described herein provide ways to identify, design, or optimize potent, selective small molecule inhibitors of DOT1L to affect selective killing of MLL-rearranged leukemias.

The method of the invention includes:

(a) generating, on a computer, a three-dimensional structure of DOT1L having the structural coordinates of Table S1 or S2;

(b) identifying amino acid residues forming an hydrophobic pocket site in the three-dimensional structure of DOT1L from step (a), wherein the hydrophobic pocket domain of DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr312 according to Table S1 or S2;

(c) generating a three-dimensional model of the active site;

(d) designing and/or selecting a compound that potentially binds to the active site using the three-dimensional model of the active site; and

(e) synthesizing and/or choosing the potential binding compound.

The method can further include contacting the identified candidate inhibitor with the DOT1L in order to determine the effect of the inhibitor on DOT1L enzymatic activity, e.g., by evaluating the residence time, K_(i) value, or in an in vivo study.

The invention also features a method of identifying a drug candidate for the treatment of a disease, the method comprising:

a) using the atomic coordinates set forth in Table S1 or S2 to form a three-dimensional structure of DOT1L;

b) selecting a test compound having the best fit with the structure of DOT1L; and

c) assaying the ability of the test compound to modulate DOT1L activity, wherein a test compound that modulates DOT1L activity is considered a drug candidate for treating a disease.

The invention also features a method for designing, identifying, and/or optimizing a candidate DOT1L inhibitor compound or complex. The method comprises:

(a) generating a crystal structure, a three-dimensional model of DOT1L, or obtaining the structure coordinates of DOT1L in complex with the candidate DOT1L inhibitor compound or complex, and

(b) determining if the candidate DOT1L inhibitor compound or complex induces a conformational adaptation and/or a hydrophobic binding site of the DOT1L from the three-dimensional model.

In another aspect, the invention features a method of locating a binding site of a candidate DOT1L inhibitor compound or complex that modulates the activity of human DOT1L.

The method comprises:

(a) obtaining X-ray diffraction data for a crystal of human DOT1L in complex with SAM or SAH or a compound of Formula (I);

(b) determining X-ray diffraction data for a crystal of human DOT1L in complex with candidate DOT1L inhibitor compound or complex or an analog or a derivative thereof;

(c) subtracting the X-ray diffraction data obtained in step (a) from the X-ray diffraction data obtained in step (b) to obtain the difference in the X-ray diffraction data;

(d) obtaining phases that correspond to X-ray diffraction data obtained in step (a);

(e) utilizing the phases obtained in step (d) and the difference in the X-ray diffraction data obtained in step (c) to compute a difference Fourier image of the candidate inhibitor; and

(f) locating the binding site of the candidate inhibitor to human DOT1L based on the computations obtained in step (e).

In the above method of locating a binding site, the crystal in step (a) includes human DOT1L in complex with SAM or SAH, or Compound D16 or A2. In one embodiment, the DOT1L-inhibitor complex in step (b) comprises the hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO: 1 and the SAM binding pocket which comprises amino acid residues 135-241 of SEQ ID NO: 1.

In yet another aspect, the invention features a method for designing, identifying, and/or optimizing a candidate DOT1L inhibitor compound or complex that interacts with all or a part of a hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO: 1 and the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO: 1. The method includes

(a) producing the structure coordinates of the hydrophobic binding pocket of DOT1L in silico comprising the means for generating three-dimensional structural information from the coordinates;

(b) designing, selecting and/or optimizing the candidate DOT1L inhibitor compound or complex by performing a fitting operation between the candidate DOT1L inhibitor compound or complex and the three-dimensional structural information of all or part of the hydrophobic binding pocket or DOT1L protein; and

(c) optionally employing computerized and/or reiterative steps.

The methods above include one or more of the following features:

For example, the SAM binding pocket of human DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Asp161, Gly163, Glu 186, Asp222, and Asn241. For example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acids according to Table S1 or S2.

For example, the SAM binding pocket of human DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Val135, Thr139, Asp161, Gly163, Gln168, Glu 186, Asp222, and Asn241. For example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acids according to Table S1 or S2. The SAM binding pocket of human DOT1L is further characterized by the crystallography coordinates of human DOT1L amino acid Phe223, for example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acid according to Table S1 or S2.

For example, the hydrophobic pocket domain of human DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr 312, for example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acids according to Table S1 or S2. The hydrophobic pocket domain of human DOT1L is further characterized by the crystallography coordinates of human DOT1L amino acid Thr139, Val144, Val169, Phe239, Val240, Asn241, Val267, Ser268, or Ser269, or combination thereof, for example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acid according to Table S1 or S2.

For example, the SAM binding pocket or the hydrophobic pocket domain of human DOT1L is characterized by the ligand plot as shown in any of FIGS. 6-9.

For example, the binding affinity (K_(i)) of the compound to human DOT1L is not greater than 50 μM, not greater than 10 μM, not greater than 5 μM, not greater than 2.5 μM, or not greater than 1 μM.

The term “associating with” refers to a condition of proximity between a chemical entity or compound, or portions thereof, and a binding pocket or binding site on a protein. The association may be non-covalent, wherein the juxtaposition is energetically favored by hydrogen bonding, hydrophobic, van der Waals or electrostatic interactions, or it may be covalent.

The term “binding pocket” or “binding site” of DOT1L refers to a region of DOT1L or a molecular complex comprising DOT1L that, as a result of the primary amino acid sequence of human DOT1L and/or its three-dimensional shape, favorably associates with another chemical entity. The term “pocket” includes, but is not limited to, a cleft, channel or site. The shape of a binding pocket may be largely pre-formed before binding of a chemical entity, may be formed simultaneously with binding of a chemical entity, or may be formed by the binding of another chemical entity to a different binding pocket of the molecule, which in turn induces a change in shape of the binding pocket.

The term “chemical entity” refers to chemical compounds, complexes of at least two chemical compounds, and fragments of such compounds or complexes. The chemical entity can be, for example, a ligand, substrate, nucleotide triphosphate, nucleotide diphosphate, phosphate, nucleotide, agonist, antagonist, inhibitor, antibody, peptide, protein or drug. In one embodiment, the chemical entity is an inhibitor or substrate for the active site.

The term “DOT1L complex” or the like refers to a molecular complex formed by associating the DOT1L protein with a chemical entity, for example, a ligand, a substrate, nucleotide triphosphate, nucleotide diphosphate, phosphate, an agonist or antagonist, inhibitor, antibody, drug or compound.

As used herein, the term “inhibitor complex” or the like refers to an association of two or more chemical compounds which can inhibit DOT1L activity. For example, an inhibitor complex is a complex of a compound having the adenosine-like moiety and another compound having a R₉ group and the complex does not have the linker group T.

The term “root mean square deviation” means the square root of the arithmetic mean of the squares of the deviations from the mean.

As used herein, the term “hydrogen bond” refers to two hydrophilic atoms (either O or N), which share a hydrogen that is covalently bonded to only one atom, while interacting with the other.

As used herein, the term “hydrophobic interaction” refers to interactions made by two hydrophobic residues or atoms (such as carbon).

As used herein, the term “crystallography coordinates” or “structure coordinates” refers to mathematical coordinates that describe the positions of atoms in crystals of hDOT1L in Protein Data Bank (PDB) format, including X, Y, Z and B, for each atom. The diffraction data obtained from the crystals are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps may be used to establish the positions (i.e. coordinates X, Y and Z) of the individual atoms within the crystal.

As used herein, the term “ligand” refers to any molecule, or chemical entity, which binds with or to DOT1L, a subunit of DOT1L, a domain of DOT1L, a target structural motif of DOT1L, or a fragment of DOT1L. Thus, ligands include, but are not limited to, modulators of DOT1L activity such as small molecule inhibitors, small molecule agonists, and small molecule inverse agonists, for example.

As used herein, the term “small molecule inhibitor” refers to ligands useful in the present invention having the ability to modulate a measurable amount of DOT1L activity. For example, a small molecule inhibitor has MW of less than 10,000 Daltons, and preferably less than 5,000 Daltons.

As used herein, the term “homolog” refers to the DOT1L protein molecule or the nucleic acid molecule which encodes the protein, or a functional domain from said protein from a first source having at least about 70% or 75% sequence identity, or at least about 80% sequence identity, or more preferably at least about 85% sequence identity, or even more preferably at least about 90% sequence identity, and most preferably at least about 95%, 97% or 99% sequence identity, with the amino acid sequence of the protein, the encoding nucleic acid molecule, or any functional domain thereof, from a second source. The second source may be a version of the molecule from the first source that has been genetically altered by any available means to change the primary amino acid or nucleotide sequence or may be from the same or a different species than that of the first source.

As used herein, the term “active site” refers to regions on DOT1L or a structural motif of DOT1L that are directly involved in the function or activity of human DOT1L.

The term “part of a binding pocket” refers to less than all of the amino acid residues that define the binding pocket. The structure coordinates of amino acid residues that constitute part of a binding pocket may be specific for defining the chemical environment of the binding pocket, or useful in designing fragments of an inhibitor that may interact with those residues.

For example, the portion of amino acid residues may be key residues that play a role in ligand binding, or may be residues that are spatially related and define a three-dimensional compartment of the binding pocket. The amino acid residues may be contiguous or non-contiguous in primary sequence. In one embodiment, part of the binding pocket has at least two amino acid residues, preferably at least three, six, eight, ten, fourteen or fifteen amino acid residues.

In one aspect, a candidate which can be identified or optimized as a DOT1L inhibitor by the method of the invention is a compound of Formula (I) below or a pharmaceutically acceptable salt or ester thereof:

wherein,

Nuc is a nucleoside moiety (e.g., an adenosine-like moiety) or an analog or a derivative thereof,

T is a linker group of a 6-10 carbon atoms, in which one or more carbon atoms are optionally replaced with a heteroatom and T is optionally substituted;

Nuc-T is capable of binding within the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO: 1; and

R₉ is a group such that R₉ induces a conformational adaptation in human DOT1L, wherein the conformational adaptation is the formation of a hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO: 1

The compound of Formula (I) may include one or more of the following features:

For example, R₉ is a group such that R₉ induces a residence time of the compound greater than 20 seconds in a complex formed of the compound and human DOT1L.

For example, R₉ is a group such that R₉ induces a conformational adaptation in human DOT1L, wherein the conformational adaptation is the formation of a hydrophobic pocket domain which is characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr312, wherein the crystallography coordinates are within about a root mean square deviation of not more than about 2 Å from the backbone atoms of the amino acids according to Table S1 or S2;

For example, Nuc is an adenosine-like moiety.

For example, the adenosine-like moiety can be

which:

A is O or CH₂;

each of G and J, independently, is H, halo, C(O)OH, C(O)O—C₁-C₆ alkyl or OR_(a), R_(a) being H, C₁-C₆ alkyl, C(O)—C₁-C₆ alkyl, or silyl, wherein C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl;

-   -   each X independently is N or CR_(x), in which R_(x) is H, halo,         hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆         alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅         cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5         to 6-membered heteroaryl, and R_(S1) being optionally         substituted with one or more substituents selected from the         group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆         alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,         C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl,         and 5 to 6-membered heteroaryl;

each of R₁ and R₂, independently is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₈ cycloalkyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₅ cycloalkyl; and

Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl.

For example, the adenosine-like moiety is

For example, the residence time of the compound in the DOT1L-compound complex is ≧50 seconds, ≧100 seconds, ≧2 minutes, ≧10 minutes, ≧30 minutes, ≧1 hr, ≧5 hr, ≧10 hr, ≧20 hr, or ≧30 hr.

For example, the compound has a residence time in the DOT1L-compound complex not shorter than that of Compound D16.

For example, the compound has a residence time in the DOT1L-compound complex not shorter than that of Compound A2.

For example, the SAM binding pocket of human DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Asp161, Gly163, Glu 186, Asp222, and Asn241. For example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acids according to Table S1 or S2.

For example, the SAM binding pocket of human DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Val135, Thr139, Asp161, Gly163, Gln168, Glu 186, Asp222, and Asn241. For example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acids according to Table S1 or S2. The SAM binding pocket of human DOT1L is further characterized by the crystallography coordinates of human DOT1L amino acid Phe223. For example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acid according to Table S1 or S2.

For example, the hydrophobic pocket domain of human DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr 312. For example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acids according to Table S1 or S2. The hydrophobic pocket domain of human DOT1L is further characterized by the crystallography coordinates of human DOT1L amino acid Thr139, Val144, Val169, Phe239, Val240, Asn241, Val267, Ser268, or Ser269, or combination thereof, for example, the crystallography coordinates are within about a root mean square deviation of not more than about 3 Å (e.g., not more than about 2.5 Å, not more than about 2 Å, or not more than about 1.5 Å) from the backbone atoms of the amino acid according to Table S1 or S2.

For example, the SAM binding pocket or the hydrophobic pocket domain of human DOT1L is characterized by the ligand plot as shown in any of FIGS. 6-9.

For example, the binding affinity (K_(i)) of the compound to human DOT1L is not greater than 50 μM, not greater than 10 μM, not greater than 5 μM, not greater than 2.5 μM, or not greater than 1 μM.

For example, in Formula (I), R₉ comprises C₆-C₁₀ aryl or 5 to 10-membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of unsubstituted or substituted t-butyl, CF₃, cyclohexyl, C₆-C₁₀ aryl, and 5 to 10-membered heteroaryl.

For example, in Formula (I), R₉ is selected from the group consisting of

For example, the compound is of Formula (II):

wherein,

A is O or CH₂;

each of G and J, independently, is H, halo, C(O)OH, C(O)O—C₁-C₆ alkyl or OR_(a), R_(a) being H, C₁-C₆ alkyl, C(O)—C₁-C₆ alkyl, or silyl, wherein C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl;

each X independently is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

each of R₁ and R₂, independently is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₈ cycloalkyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₅ cycloalkyl; and

Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl.

In Formula (I) or (II), T is —CH₂-L₁-L₂-L₃-, with L₃ connected to R₉, wherein:

L₁ is N(Y), S, SO, or SO₂;

L₂ is CO or absent when L₁ is N(Y), or L₂ is absent when L₁ is S, SO, or SO₂, in which Y is H, R_(d), SO₂R_(d), or COR_(d) when L₂ is absent, or Y is H or R_(d) when L₂ is CO, R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, OR_(d′), OCOR_(d′), and N(R_(d′))₂, and with C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl; each R_(d′) independently being H, C₁-C₆ alkyl, silyl, C₁-C₆ alkyl-C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 5 to 6-membered heteroaryl, aralkyl, or heteroaralkyl;

L₃ is —(CR₄R₅)_(n)(CR₆R₇)_(m)— or —(CR₄R₅)_(n)-unsubstituted or substituted C₃-C₈ cycloalkyl-(CR₆R₇)_(m)—, with (CR₆R₇)_(m) connected to R₉;

each of R₄, R₅, R₆, and R₇, independently, is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; or two geminal R₄ and R₅ or two geminal R₆ and R₇ taken together are ethylene, propylene or butylene;

m is 0, 1, or 2; and

n is 0, 1, or 2.

For example, in Formula (I) or (II), R₉ is

in which:

each of R_(e), R_(f), R_(g), and R_(h), independently is -M₂-T₂, in which M₂ is a bond, SO₂, SO, S, CO, CO₂, O, O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, NH, or N(R_(t)), R_(t) being C₁-C₆ alkyl, and T₂ is H, halo, or R_(S4), R_(S4) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, R_(t), and R_(S4) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R_(i) is H or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl,

D is O, NR_(j), or CR_(j)R_(k), each of R_(j) and R_(k) independently being H or C₁-C₆ alkyl, or R_(j) and R_(k) taken together, with the carbon atom to which they are attached, form a C₃-C₁₀ cycloalkyl ring, and E is -M₃-T₃, M₃ being a bond or C₁-C₆ alkyl linker optionally substituted with halo or cyano, T₃ being C₃-C₁₄ carbocycle or 4 to 14-membered heterocycle, and T₃ being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, halo, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C₁-C₆ alkoxyl.

For example, the compound is of formula (IIIa) or (IIIb):

wherein R₃ is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), and q is 0, 1, 2, 3, or 4.

For example, the compound is of formula (IIIa) and R₉ is

For example, the compound is of formula (IIIb) and R₉ is

Compounds that are identified as DOT1L inhibitors by the method described herein can also include those of Formula (IIa) or (IIb)

or a pharmaceutically acceptable salt or ester thereof, wherein:

A is O or CH₂;

each of G and J, independently, is H, halo, C(O)OH, C(O)O—C₁-C₆ alkyl or OR_(a), R_(a) being H, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl, wherein C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl;

Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

X is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

L₁ is N(Y), S, SO, or SO₂;

L₂ is CO or absent when L₁ is N(Y) or L₂ is absent when L₁ is S, SO, or SO₂, in which Y is H, R_(d), SO₂R_(d), or COR_(d) when L₂ is absent, or Y is H or R_(d) when L₂ is CO, R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;

each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇, independently, is H, halo, hydroxyl, carboxyl, cyano, R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₅ cycloalkyl;

R₉ is

in which each of R_(e), R_(f), R_(g), and R_(h), independently is -M₂-T₂, in which M₂ is a bond, SO₂, SO, S, CO, CO₂, O, O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, NH, or N(R_(t)), R_(t) being C₁-C₆ alkyl, and T₂ is H, halo, or R_(S4), R_(S4) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, R_(t), and R_(S4) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R_(i) is H or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR_(j), or CR_(j)R_(k), each of R_(j) and R_(k) independently being H or C₁-C₆ alkyl, or R_(j) and R_(k) taken together, with the carbon atom to which they are attached, form a C₃-C₁₀ cycloalkyl ring, and E is -M₃-T₃, M₃ being a bond or C₁-C₆ alkyl linker optionally substituted with halo or cyano, T₃ being C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T₃ being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, halo, C₁-C₆ alkoxycarbonyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C₁-C₆ alkoxyl;

q is 0, 1, 2, 3, or 4;

m is 0, 1, or 2; and

n is 0, 1, or 2.

For example, the sum of m and n is at least 1.

For example, m is 1 or 2 and n is 0.

For example, m is 2 and n is 0

For example, A is CH₂.

For example, A is O.

For example, L₁ is N(Y).

For example, L₁ is SO or SO₂.

For example, Y is R_(d).

For example, R_(d) is C₁-C₆ alkyl.

For example, L₂ is absent.

For example, each of G and J independently is OR_(a).

For example, R_(a) is H.

For example, R₉ is

For example, R₉ is

For example, at least one of R_(e), R_(f), R_(g), and R_(h) is halo (such as F, Cl, and Br), C₁-C₆ alkoxyl optionally substituted with one or more halo (such as OCH₃, OCH₂CH₃, O-iPr, and OCF₃), C₁-C₆ alkylsulfonyl optionally substituted with one or more halo (such as SO₂CF₃), or C₁-C₆ alkyl optionally substituted with one or more halo (such as CH₃, i-propyl, n-butyl, and CF₃).

For example, R_(i) is H or C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example,

is unsubstituted benzimidazolyl or one of the following groups:

For example, R₉ is

For example, D is O.

For example, D is NR_(j).

For example, R_(j) is H.

For example, D is CR_(j)R_(k).

For example, each of R_(j) and R_(k) is H.

For example, E is -M₃-T₃, in which M₃ is a bond or C₁-C₃ alkyl linker, T₃ is phenyl, naphthyl, thienyl, cyclopropyl, or cyclohexyl, and T₃ is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with C₁-C₄ alkyl, 5 to 6-membered heteroaryl optionally substituted with C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, C₁-C₆ alkoxycarbonyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl.

For example, T₃ is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, nitro, C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl), C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylsulfonyl, C₆-C₁₀ aryl (e.g., phenyl or naphthyl), and C₆-C₁₀ aryloxyl, and C₇-C₁₄ alkylaryl.

For example, E is

For example, X is N.

For example, X is CRY.

For example, X is CH.

For example, Q is NH₂ or NHR_(b), in which R_(b) is -M₁-T₁, M₁ being a bond or C₁-C₆ alkyl linker and T being C₃-C₅ cycloalkyl.

For example, Q is H.

For example, R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each H.

For example, when R₈ is halo and is attached to the same carbon atom as J, then J is not hydroxyl.

For example, when R₈ is halo and is attached to the same carbon atom as G, then G is not hydroxyl.

For example, T₂ is not halo when M₂ is SO₂, SO, S, CO or O.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a heteroatom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a N atom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a C atom.

Compounds that are identified as DOT1L inhibitors by the method described herein can also include those of Formula (IIc) or (IId):

or a pharmaceutically acceptable salt or ester thereof, wherein the variables are defined herein as for Formula (IIa) or (IIb).

The compound of Formula (II) include those of Formula (IIIa), or (IIIb):

or a pharmaceutically acceptable salt or ester thereof, wherein:

A is O or CH₂;

Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl, or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T1 is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

X is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

L₁ is N(Y), S, SO, or SO₂;

L₂ is CO or absent when L₁ is N(Y) or L₂ is absent when L₁ is S, SO, or SO₂, in which Y is H, R_(d), SO₂R_(d), or COR_(d) when L₂ is absent, or Y is H or R_(d) when L₂ is CO, R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;

each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇, independently, is H, halo, hydroxyl, carboxyl, cyano, R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl;

R₉ is

in which each of R_(e), R_(f), R_(g), and R_(h), independently is -M₂-T₂, in which M₂ is a bond, SO₂, SO, S, CO, CO₂, O, O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, NH, or N(R_(t)), R_(t) being C₁-C₆ alkyl, and T₂ is H, halo, or R_(S4), R_(S4) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, R_(t), and R_(S4) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R_(i) is H or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR_(j), or CR_(j)R_(k), each of R_(j) and R_(k) independently being H or C₁-C₆ alkyl, or R_(j) and R_(k) taken together, with the carbon atom to which they are attached, form a C₃-C₁₀ cycloalkyl ring, and E is -M₃-T₃, M₃ being a bond or C₁-C₆ alkyl linker optionally substituted with halo or cyano, T₃ being C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T₃ being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, halo, C₁-C₆ alkoxycarbonyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C₁-C₆ alkoxyl;

q is 0, 1, 2, 3, or 4;

m is 0, 1, or 2; and

n is 0, 1, or 2.

For example, the sum of m and n is at least 1.

For example, m is 1 or 2 and n is 0.

For example, m is 2 and n is 0

For example, A is CH₂.

For example, A is O.

For example, L₁ is N(Y).

For example, L₁ is SO or SO₂.

For example, Y is R_(d).

For example, R_(d) is C₁-C₆ alkyl.

For example, L₂ is absent.

For example, R₉ is

For example, R₉ is

For example, at least one of R_(e), R_(f), R_(g), and R_(h) is halo (such as F, Cl, and Br), C₁-C₆ alkoxyl optionally substituted with one or more halo (such as OCH₃, OCH₂CH₃, O-iPr, and OCF₃), C₁-C₆ alkylsulfonyl optionally substituted with one or more halo (such as SO₂CF₃), or C₁-C₆ alkyl optionally substituted with one or more halo (such as CH₃, i-propyl, n-butyl, and CF₃).

For example, R_(i) is H or C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl).

For example,

is unsubstituted benzimidazolyl or one of the following groups:

For example, R₉ is

For example, D is O.

For example, D is NR_(j).

For example, R_(j) is H.

For example, D is CR_(j)R_(k).

For example, each of R_(j) and R_(k) is H.

For example, E is -M₃-T₃, in which M₃ is a bond or C₁-C₃ alkyl linker, T₃ is phenyl, naphthyl, thienyl, cyclopropyl, or cyclohexyl, and T₃ is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with C₁-C₄ alkyl, 5 to 6-membered heteroaryl optionally substituted with C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl.

For example, T₃ is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, nitro, C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl), C1-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylsulfonyl, C₆-C₁₀ aryl (e.g., phenyl or naphthyl), and C₆-C₁₀ aryloxyl, and C₇-C₁₄ alkylaryl.

For example, E is

For example, X is N.

For example, X is CR_(x).

For example, X is CH.

For example, Q is NH₂ or NHR_(b), in which R_(b) is -M₁-T₁, M₁ being a bond or C₁-C₆ alkyl linker and T₁ being C₃-C₅ cycloalkyl.

For example, Q is H.

For example, R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each H.

For example, when R₈ is halo and is attached to the same carbon atom as J, then J is not hydroxyl.

For example, when R₈ is halo and is attached to the same carbon atom as G, then G is not hydroxyl.

For example, T₂ is not halo when M₂ is SO₂, SO, S, CO or O.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a heteroatom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a N atom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a C atom.

The present invention provides the compounds of Formula (IVa), (IVb), (IVd), or (IVe):

or a pharmaceutically acceptable salt or ester thereof, wherein:

A is O or CH₂;

each of G and J, independently, is H, halo, C(O)OH, C(O)O—C₁-C₆ alkyl or OR_(a), R_(a) being H, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl, wherein C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₅ cycloalkyl;

Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

X is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

L₁ is N(Y), S, SO, or SO₂;

L₂ is CO or absent when L₁ is N(Y) or L₂ is absent when L₁ is S, SO, or SO₂, in which Y is H, R_(d), SO₂R_(d), or COR_(d) when L₂ is absent, or Y is H or R_(d) when L₂ is CO, R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;

each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇, independently, is H, halo, hydroxyl, carboxyl, cyano, R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl;

each of R_(e), R_(f), R_(g), and R_(h), independently is -M₂-T₂, in which M₂ is a bond, SO₂, SO, S, CO, CO₂, O, O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, NH, or N(R_(t)), R_(t) being C₁-C₆ alkyl, and T₂ is H, halo, or R_(S4), R_(S4) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, R_(t), and R_(S4) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl,

R_(i) is H or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

q is 0, 1, 2, 3, or 4;

m is 0, 1, or 2; and

n is 0, 1, or 2.

For example, the sum of m and n is at least 1.

For example, m is 1 or 2 and n is 0.

For example, m is 2 and n is 0

For example, A is CH₂.

For example, A is O.

For example, L₁ is N(Y).

For example, L₁ is SO or SO₂.

For example, Y is R_(d).

For example, R_(d) is C₁-C₆ alkyl.

For example, L₂ is absent.

For example, each of G and J independently is OR_(a).

For example, R_(a) is H.

For example, at least one of R_(e), R_(f), R_(g), and R_(h) is halo (such as F, Cl, and Br), C₁-C₆ alkoxyl optionally substituted with one or more halo (such as OCH₃, OCH₂CH₃, O-iPr, and OCF₃), C₁-C₆ alkylsulfonyl optionally substituted with one or more halo (such as SO₂CF₃), or C₁-C₆ alkyl optionally substituted with one or more halo (such as CH₃, i-propyl, n-butyl, and CF₃).

For example, R_(i) is H or C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example,

is unsubstituted benzimidazolyl or one of the following groups:

For example, X is N.

For example, X is CR_(x).

For example, X is CH.

For example, Q is NH₂ or NHR_(b), in which R_(b) is -M₁-T₁, M₁ being a bond or C₁-C₆ alkyl linker and T₁ being C₃-C₈ cycloalkyl.

For example, Q is H.

For example, R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each H.

For example, when R₈ is halo and is attached to the same carbon atom as J, then J is not hydroxyl.

For example, when R₈ is halo and is attached to the same carbon atom as G, then G is not hydroxyl.

For example, T₂ is not halo when M₂ is SO₂, SO, S, CO or O.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a heteroatom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a N atom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a C atom.

The present invention provides the compounds of Formula (IVc) or (IVf):

or a pharmaceutically acceptable salt or ester thereof, wherein:

A is O or CH₂;

each of G and J, independently, is H, halo, C(O)OH, C(O)O—C₁-C₆ alkyl or OR_(a), R_(a) being H, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl, wherein C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl;

Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

X is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

L₁ is N(Y), S, SO, or SO₂;

L₂ is CO or absent when L₁ is N(Y) or L₂ is absent when L₁ is S, SO, or SO₂, in which Y is H, R_(d), SO₂R_(d), or COR_(d) when L₂ is absent, or Y is H or R_(d) when L₂ is CO, R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;

each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇, independently, is H, halo, hydroxyl, carboxyl, cyano, R_(S2), R_(S2) being amino, C1-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;

R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₅ cycloalkyl;

D is O, NR_(j), or CR_(j)R_(k), each of R_(j) and R_(k) independently being H or C₁-C₆ alkyl, or R_(j) and R_(k) taken together, with the carbon atom to which they are attached, form a C₃-C₁₀ cycloalkyl ring;

E is -M₃-T₃, M₃ being a bond or C₁-C₆ alkyl linker optionally substituted with halo or cyano, T₃ being C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T₃ being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, halo, C₁-C₆ alkoxycarbonyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C₁-C₆ alkoxyl;

q is 0, 1, 2, 3, or 4;

m is 0, 1, or 2; and

n is 0, 1, or 2.

For example, the sum of m and n is at least 1.

For example, m is 1 or 2 and n is 0.

For example, m is 2 and n is 0

For example, A is CH₂.

For example, A is O.

For example, L₁ is N(Y).

For example, L₁ is SO or SO₂.

For example, Y is R_(d).

For example, R_(d) is C1-C₆ alkyl.

For example, L₂ is absent.

For example, each of G and J independently is OR_(a).

For example, R_(a) is H.

For example, D is O.

For example, D is NR_(j).

For example, R_(j) is H.

For example, D is CR_(j)R_(k).

For example, each of R_(j) and R_(k) is H.

For example, E is -M₃-T₃, in which M₃ is a bond or C₁-C₃ alkyl linker, T₃ is phenyl, naphthyl, thienyl, cyclopropyl, or cyclohexyl, and T₃ is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with C₁-C₄ alkyl, 5 to 6-membered heteroaryl optionally substituted with C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl.

For example, T₃ is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, nitro, C1-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl), C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylsulfonyl, C₆-C₁₀ aryl (e.g., phenyl or naphthyl), and C₆-C₁₀ aryloxyl, and C₇-C₁₄ alkylaryl.

For example, E is

For example, X is N.

For example, X is CR_(x).

For example, X is CH.

For example, Q is NH₂ or NHR_(b), in which R_(b) is -M₁-T₁, M₁ being a bond or C₁-C₆ alkyl linker and T₁ being C₃-C₈ cycloalkyl.

For example, Q is H.

For example, R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each H.

For example, when R₈ is halo and is attached to the same carbon atom as J, then J is not hydroxyl.

For example, when R₈ is halo and is attached to the same carbon atom as G, then G is not hydroxyl.

For example, T₂ is not halo when M₂ is SO₂, SO, S, CO or O.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a heteroatom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a N atom.

For example, T₂ is a 4-8 membered heterocycloalkyl which is bound to M₂ via a C atom.

The invention also relates to a compound of Formula (IV) or its N-oxide or a pharmaceutically acceptable salt thereof:

wherein A is O or CH₂; Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; X is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; Y is H, R_(d), SO₂R_(d), or COR_(d), R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C6-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C1-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl; each of R₁ and R₂ independently, is H, halo, hydroxyl, carboxyl, cyano, R_(S2), R_(S2) being amino, C1-C₆ alkoxyl, C1-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; each of R_(e), R_(f), R_(g), and R_(h), independently is -M₂-T₂, in which M₂ is a bond, SO₂, SO, S, CO, CO₂, O, O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, NH, or N(R_(t)), R_(t) being C₁-C₆ alkyl, and T₂ is H, halo, or R_(S4), R_(S4) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, R_(t), and R_(S4) being optionally substituted with one or more substituents selected from halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, and m is 0, 1, or 2.

For example, A is O. In certain compounds of Formula (IV), A is O and m is 2.

In certain compounds of Formula (IV), X is N.

For example, in certain compounds, Q is NH₂ or NHR_(b), in which R_(b) is -M₁-T₁, M₁ being a bond or C₁-C₆ alkyl linker and T₁ being C₃-C₅ cycloalkyl

For example, in certain compounds of Formula (IV), R₁ and R₂ are each H.

In certain compounds of Formula (IV), Y is R_(d). For example, R_(d) is C₁-C₆ alkyl optionally substituted with C₃-C₈ cycloalkyl or halo. For example, R_(d) is C₃-C₈ cycloalkyl optionally substituted with C₁-C₆ alkyl or halo.

The invention also relates to a compound of Formula (IV), wherein at least one of R_(e), R_(f), R_(g), and R_(h) is halo, C₁-C₆ alkoxyl optionally substituted with one or more halo; C₁-C₆ alkylsulfonyl optionally substituted with one or more halo; C₁-C₆ alkyl optionally substituted with one or more substituents selected from CN, halo, C₃-C₅ cycloalkyl, hydroxy, and C₁-C₆ alkoxyl; C₃-C₈ cycloalkyl optionally substituted with one or more C₁-C₆ alkyl or CN; or 4 to 8-membered heterocycloalkyl optionally substituted with one or more substituents selected from CN, halo, hydroxy, C₁-C₆ alkyl and C₁-C₆ alkoxyl. For example, the compound of Formula (IV) has at least one of R_(e), R_(f), R_(g), and R_(h) selected from F; Cl; Br; CF₃; OCF₃; SO₂CF₃; oxetanyl optionally substituted with one or more substituents selected from CN, halo, hydroxy, C₁-C₆ alkyl and C₁-C₆ alkoxyl; C₃-C₈ cycloalkyl optionally substituted with one or more substituents selected from C₁-C₄ alkyl; and C₁-C₄ alkyl optionally substituted with one or more substituents selected from halo, C₃-C₅ cycloalkyl, hydroxy and C₁-C₆ alkoxyl.

For example, the invention relates to compounds of Formula (IV) where at least one of R_(f) and R_(g) is alkyl, optionally substituted with hydroxyl. For example, the invention relates to compounds where at least one of R_(f) and R_(g) is t-butyl substituted with hydroxyl.

The invention relates to a compound selected from Tables 1-4. The invention also relates to a salt of a compound selected from Tables 1-4. The invention also relates to an N-oxide of compound selected from Tables 1-4. The invention also relates to a salt of an N-oxide of compound selected from Tables 1-4. For example, the invention relates to a compound selected from Compounds A1-A7, A9-A109, and A111-A140.

Other compounds suitable for the methods of the invention, as well as pharmaceutical compositions and uses thereof, are described in WO2012/075381, WO2012/075492, WO2012/082436, and WO2012/75500, the contents of which are hereby incorporated by reference in their entireties.

The invention also relates to a pharmaceutical composition of a therapeutically effective amount of a compound of any of the Formulae disclosed herein and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition of a therapeutically effective amount of a salt of a compound of any of the Formulae disclosed herein and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition of a therapeutically effective amount of a hydrate of a compound of any of the Formulae disclosed herein and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition of a therapeutically effective amount of a compound selected from Tables 1-4 and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition of a therapeutically effective amount of a salt of a compound selected from Tables 1-4 and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition of a therapeutically effective amount of an N-oxide of a compound selected from Tables 1-4 and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition of a therapeutically effective amount of an N-oxide of salt of a compound selected from Tables 1-4 and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition of a therapeutically effective amount of a hydrate of a compound selected from Tables 1-4 and a pharmaceutically acceptable carrier.

The present invention provides methods of treating or preventing cancer. The present invention provides methods of treating cancer. The present invention also provides methods of preventing cancer. The method includes administering to a subject in need thereof a therapeutically effective amount of the compound of any of the Formulae disclosed herein. The cancer can be a hematological cancer. Preferably, the cancer is leukemia. More preferably, the cancer is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.

The present invention provides methods of treating or preventing a disease or disorder mediated by translocation of a gene on chromosome 11q23. The present invention provides methods of treating a disease or disorder mediated by translocation of a gene on chromosome 11q23. The present invention also provides methods of preventing a disease or disorder mediated by translocation of a gene on chromosome 11q23. The method includes administering to a subject in need thereof a therapeutically effective amount of the compound of any of the Formulae disclosed herein.

The present invention provides methods of treating or preventing a disease or disorder in which DOT -mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The present invention provides methods of treating a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The present invention also provides methods of preventing a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The method includes administering to a subject in need thereof a therapeutically effective amount of the compound of any of the Formulae disclosed herein.

The present invention provides methods of inhibiting DOT1L activity in a cell. The method includes contacting the cell with an effective amount of one or more of the compound of any of the Formulae disclosed herein.

Still another aspect of the invention relates to a method of reducing the level of Histone H3 Lysine residue 79 (H3-K79) methylation in a cell. The method includes contacting a cell with a compound of the present invention. Such method can be used to ameliorate any condition which is caused by or potentiated by the activity of DOT1 through H3-K79 methylation.

The present invention relates to use of the compounds disclosed herein in preparation of a medicament for treating or preventing cancer. The use includes a compound of any of the Formulae disclosed herein for administration to a subject in need thereof in a therapeutically effective amount. The cancer can be a hematological cancer. Preferably, the cancer is leukemia. More preferably, the cancer is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.

The present invention provides use of the compounds disclosed herein in preparation of a medicament for treating or preventing a disease or disorder mediated by translocation of a gene on chromosome 11q23. The use includes a compound of any of the Formulae disclosed herein for administration to a subject in need thereof in a therapeutically effective amount.

The present invention provides use of the compounds disclosed herein in preparation of a medicament for treating or preventing a disease or disorder in which DOT1-mediated protein methylation plays a part or a disease or disorder mediated by DOT1-mediated protein methylation. The use includes a compound of any of the Formulae disclosed herein for administration to a subject in need thereof in a therapeutically effective amount.

The present invention provides use of the compounds disclosed herein for inhibiting DOT1L activity in a cell. The use includes contacting the cell with an effective amount of one or more of the compound of any of the Formulae disclosed herein.

Still another aspect of the invention relates to a use of the compounds disclosed herein for reducing the level of Histone H3 Lysine residue 79 (H3-K79) methylation in a cell. The use includes contacting a cell with a compound of the present invention. Such use can ameliorate any condition which is caused by or potentiated by the activity of DOT1 through H3-K79 methylation.

In the formulae presented herein, the variables can be selected from the respective groups of chemical moieties later defined in the detailed description.

In addition, the invention provides methods of synthesizing the foregoing compounds. Following synthesis, a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use in modulating an epigenetic enzyme. In certain embodiments, the compounds of the present invention are useful for treating, preventing, or reducing the risk of cancer or for the manufacture of a medicament for treating, preventing, or reducing the risk of cancer. Accordingly, the compounds or the formulations can be administered, for example, via oral, parenteral, otic, ophthalmic, nasal, or topical routes, to provide an effective amount of the compound to the mammal.

Representative compounds of the present invention include compounds listed in Tables 1-4.

TABLE 1 Cmpd No. Chemical Name A1 (2R,3S,4R,5R)-2-(((3-(2-(1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-5-(6-amino-9H- purin-9-yl)tetrahydrofuran-3,4-diol A2 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A3 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A4 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-chloro-6-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A5 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-chloro-6-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A6 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-((5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)methyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A7 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(6-chloro-5-(trifluoromethyl)- 1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A8 1-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)cyclobutyl)-3-(4-tert-butylphenyl)urea A9 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(6-chloro-5- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A10 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1r,3S)-3-(2-(5- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A11 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1s,3R)-3-(2-(5- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A12 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(6-chloro-5- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A13 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl(3-(2-(5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A14 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A15 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl((3-((5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)methyl)cyclobutyl)methyl)amino)methyl)cyclopentane-1,2-diol A16 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(5-chloro-6-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A17 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(((3-(2-(5-chloro-6-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentanol A18 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((3-((5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)methyl)cyclobutyl)methyl)amino)methyl)cyclopentane-1,2-diol A19 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol A20 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(6-chloro-5-(trifluoromethyl)- 1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol A21 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((3-((6-chloro-5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)methyl)cyclobutyl)methyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol A22 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((3-((5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)methyl)cyclobutyl)methyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol A23 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5,6-dichloro-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A24 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl(3-(2-(5-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A25 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)cyclopentane-1,2-diol A26 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-bromo-1H-benzo[d]imidazol- 2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A27 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl(3-(2-(5-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A28 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1r,3S)-3-(2-(5-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A29 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl(3-(2-(5-(1-methylcyclobutyl)- 1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A30 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl((1r,3S)-3-(2-(5-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A31 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1s,3R)-3-(2-(5-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A32 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A33 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl(3-(2-(5-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A34 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl((1s,3R)-3-(2-(5-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A35 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A36 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1r,3S)-3-(2-(5-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A37 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1r,3S)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A38 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)cyclopentane-1,2-diol A39 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1s,3R)-3-(2-(5-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A40 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclopropylmethyl)amino)methyl)cyclopentane-1,2-diol A41 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol A42 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutylmethyl)amino)methyl)cyclopentane-1,2-diol A43 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutyl)amino)methyl)cyclopentane-1,2-diol A44 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclopropylmethyl)amino)methyl)cyclopentane-1,2-diol A45 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isobutyl)amino)methyl)cyclopentane-1,2-diol A46 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutyl)amino)methyl)cyclopentane-1,2-diol A47 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-bromo-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A48 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isobutyl)amino)methyl)cyclopentane-1,2-diol A49 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)cyclopentane-1,2-diol A50 (1R,2S,3R,5R)-3-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol A51 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutyl)amino)methyl)cyclopentane-1,2-diol A52 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5,6-dichloro-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A53 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isobutyl)amino)methyl)cyclopentane-1,2-diol A54 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclopropylmethyl)amino)methyl)cyclopentane-1,2-diol A55 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-bromo-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A56 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl(3-(2-(5-(trifluoromethoxy)- 1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A57 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1s,3R)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A58 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5,6-dichloro-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A59 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutylmethyl)amino)methyl)cyclopentane-1,2-diol A60 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl((1r,3S)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A61 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl((1s,3R)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A62 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl(3-(2-(5-(oxetan-3-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)cyclopentane-1,2-diol A63 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl((1r,3S)-3-(2-(5-(oxetan-3-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A64 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A65 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl((1s,3R)-3-(2-(5-(oxetan-3-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A66 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(2,2,2-trifluoroethyl)amino)methyl)cyclopentane-1,2-diol A67 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A68 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(1-methoxy-2-methylpropan-2-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A69 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A70 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(6-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol A71 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A72 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A73 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(ethyl)amino)methyl)tetrahydrofuran-3,4-diol A74 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(ethyl)amino)methyl)tetrahydrofuran-3,4-diol A75 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A76 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl((1s,3R)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A77 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(2,2,2-trifluoroethyl)amino)methyl)tetrahydrofuran-3,4-diol A78 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(2,2,2-trifluoroethyl)amino)methyl)tetrahydrofuran-3,4-diol A79 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(ethyl)amino)methyl)tetrahydrofuran-3,4-diol A80 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(2,2,2-trifluoroethyl)amino)methyl)tetrahydrofuran-3,4-diol A81 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((((1r,3R)-3-(2-(5-chloro-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentanol A82 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(2,2,2-trifluoroethyl)amino)methyl)tetrahydrofuran-3,4-diol A83 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(((3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentanol A84 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(((3-(2-(5-chloro-6-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentanol A85 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((((1s,3S)-3-(2-(5-chloro-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)cyclopentanol A86 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A87 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl((1r,3S)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A88 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)tetrahydrofuran-3,4-diol A89 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)tetrahydrofuran-3,4-diol A90 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A91 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1r,3S)-3-(2-(5-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A92 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A93 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1s,3R)-3-(2-(5-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A94 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1r,3S)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A95 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl((1s,3R)-3-(2-(5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A96 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl((1r,3S)-3-(2-(5-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A97 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl((1s,3R)-3-(2-(5-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A98 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A99 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol 1A00 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl(3-(2-(5-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A101 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((((1r,3R)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentanol A102 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(2,2,2-trifluoroethyl)amino)methyl)tetrahydrofuran-3,4-diol A103 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((((1s,3S)-3-(2-(5-chloro-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentanol A104 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((((1s,3S)-3-(2-(5-(tert-butyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentanol A105 (1R,2R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((((1r,3R)-3-(2-(5-chloro-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentanol A106 (1r,3S)-N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-(2- (5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)-N-isopropylcyclobutanamine oxide A107 (R,1s,3R)-N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3- (2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)-N-isopropylcyclobutanamine oxide A108 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(1-hydroxy-2-methylpropan-2-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A109 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-(1-hydroxy-2-methylpropan-2-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A110 1-((3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)cyclobutyl)methyl)-3-(4-(tert-butyl)phenyl)urea A111 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A112 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-cyclopropyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A113 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl(3-(2-(5-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A114 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A115 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A116 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-cyclopropyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A117 1-(2-(2-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclobutanecarbonitrile A118 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl(3-(2-(5-(1-methoxy-2-methylpropan-2-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A119 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-cyclopropyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol A120 2-(2-(2-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methylpropanenitrile A121 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1s,3R)-3-(2-(5-(1-methoxy-2-methylpropan-2- yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A122 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1r,3S)-3-(2-(5-(1-methoxy-2-methylpropan-2- yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A123 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1s,3R)-3-(2-(5-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A124 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl((1r,3S)-3-(2-(5-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A125 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A126 1-(2-(2-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclopropanecarbonitrile A127 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-cyclopropyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A128 2-(2-(2-((1S,3r)-3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methylpropanenitrile A129 2-(2-(2-((1R,3s)-3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methylpropanenitrile A130 1-(2-(2-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclopropanecarbonitrile A131 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A132 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-cyclobutyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A133 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-cyclopropyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A134 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1s,3R)-3-(2-(5-cyclopropyl-1H-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol A135 1-(2-(2-((1S,3r)-3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclopropanecarbonitrile A136 1-(2-(2-((1R,3s)-3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclopropanecarbonitrile A137 1-(2-(2-((1S,3r)-3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclopropanecarbonitrile A138 1-(2-(2-((1R,3s)-3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)cyclobutyl)ethyl)-1H-benzo[d]imidazol-5-yl)cyclopropanecarbonitrile A139 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isopropyl(3-(2-(5-(1-methylcyclopropyl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol A140 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(1-methoxy-2-methylpropan-2-yl)-1H- benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)tetrahydrofuran-3,4-diol

TABLE 2 Cmpd. No. Chemical Name B1 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((4-(5-tert-butyl-1H-benzo[d]imidazol- 2-yl)butyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol B2 (1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((4-(5-tert-butyl-1H-benzo[d]imidazol- 2-yl)butyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol B3 1-(3-((((1S,2R,3S,4R)-4-(6-amino-9H-purin-9-yl)-2,3- dihydroxycyclopentyl)methyl)(methyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea B4 (1S,2R,3R,5R)-3-(((4-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)butyl)(isopropyl)amino)methyl)-5-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol B5 (1S,2R,3R,5R)-3-(((4-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)butyl)(methyl)amino)methyl)-5-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol B6 (1R,2S,3R,5R)-3-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((isopropyl(4-(6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)butyl)amino)methyl)cyclopentane-1,2-diol B7 (1R,2S,3R,5R)-3-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((methyl(4-(6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)butyl)amino)methyl)cyclopentane-1,2-diol B8 (1R,2S,3R,5R)-3-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((4-(5,6-dichloro-1H- benzo[d]imidazol-2-yl)butyl)(methyl)amino)methyl)cyclopentane-1,2-diol B9 (1R,2S,3R,5R)-3-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((4-(5,6-dichloro-1H- benzo[d]imidazol-2-yl)butyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol trihydrochloride B10 1-(3-((((1R,2R,3S,4R)-4-(6-amino-9H-purin-9-yl)-2,3- dihydroxycyclopentyl)methyl)(methyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea B11 N-(4-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)butyl)-N-(((1R,2R,3S,4R)-4-(4-(cyclopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)methyl)methanesulfonamide B12 N-(4-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)butyl)-N-(((1R,2R,3S,4R)-4-(4- (cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3- dihydroxycyclopentyl)methyl)methanesulfonamide B13 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((4-(6-chloro-5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)butyl)(methyl)amino)methyl)cyclopentane-1,2-diol B14 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((4-(6-chloro-5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)butyl)(isopropyl)amino)methyl)cyclopentane-1,2-diol B15 N-(((1R,2R,3S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)methyl)-N- (4-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)butyl)methanesulfonamide B16 N-(((1R,2R,3S,4R)-4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3- dihydroxycyclopentyl)methyl)-N-(4-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)butyl)methanesulfonamide B17 N-(((1R,2R,3S,4R)-4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3- dihydroxycyclopentyl)methyl)-N-(4-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)butyl)methanesulfonamide

TABLE 3 SAH

C1 

C2 

C64 

C79 

C80 

C81 

C83 

C84 

C85 

C86 

C89 

C90 

C91 

C92 

C93 

C94 

C95 

C96 

C97 

C98 

C112

C113

C114

C115

C116

C117

C118

C122

C123

C124

C125

C126

C127

C128

C129

C130

C131

C140

C141

C142

C143

TABLE 4 D1 

D2 

D3 

D4 

D5 

D6 

D7 

D8 

D9 

D10

D11

D12

D13

D14

D15

D16

D17

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆ alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups.

As used herein, the term “cycloalkyl” refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring system having 3 to 30 carbon atoms (e.g., C₃-C₁₀). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl. The term “heterocycloalkyl” refers to a saturated or unsaturated nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se). Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

The term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

An “arylalkyl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). An “alkylaryl” moiety is an aryl substituted with an alkyl (e.g., methylphenyl).

As used herein, “alkyl linker” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl linker is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl linker groups.

“Alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.

“Alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.

Other optionally substituted moieties (such as optionally substituted alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents.

“Aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthalenyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.” As used herein, the term “heteroaryl” is intended to include a stable 5- or 6-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), where p=1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

In the case of multicyclic aromatic rings, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), although all of the rings may be aromatic (e.g., quinoline). The second ring can also be fused or bridged.

As used herein, “carbocycle” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.

Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and [2.2.2]bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.

As used herein, “heterocycle” includes any ring structure (saturated or partially unsaturated) which contains at least one ring heteroatom (e.g., N, O or S). Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted,” as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., ═O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

When any variable (e.g., R₁) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R₁ moieties, then the group may optionally be substituted with up to two R₁ moieties and R₁ at each occurrence is selected independently from the definition of R₁. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

Compounds of the present invention that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the present invention. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N→O or N⁺—O⁻). Furthermore, in other instances, the nitrogens in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R is substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like. In addition, a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present invention. Furthermore, so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present invention.

“Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

It is to be understood that the compounds of the present invention may be depicted as different chiral isomers or geometric isomers. It should also be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present invention, and the naming of the compounds does not exclude any isomeric forms.

For example, compounds of Formula (II) include those of the following chiral isomers and geometric isomers.

Furthermore, the structures and other compounds discussed in this invention include all atropic isomers thereof. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

“Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine. Benzimidazoles also exhibit tautomerism, when the benzimidazole contains one or more substituents in the 4, 5, 6 or 7 positions, the possibility of different isomers arises. For example, 2,5-dimethyl-1H-benzo[d]imidazole can exist in equilibrium with its isomer 2,6-dimethyl-1H-benzo[d]imidazole via tautomerization.

Another example of tautomerism is shown below.

It is to be understood that the compounds of the present invention may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present invention, and the naming of the compounds does not exclude any tautomer form.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

Compounds of the invention may be crystalline, semi-crystalline, non-crystalline, amorphous, mesomorphous, etc.

The compounds of any of the Formulae disclosed herein or the DOT1L inhibitors identified by the methods of the invention include the compounds themselves, as well as their N-oxides, salts, their solvates, and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on the compound or inhibitor (e.g., a substituted nucleoside compound such as a substituted purine or 7-deazapurine compound). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on the compound or inhibitor (e.g., a substituted nucleoside compound such as a substituted purine or 7-deazapurine compound). Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The compound or inhibitor (e.g., a substituted nucleoside compound such as a substituted purine or 7-deazapurine compound) also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active substituted nucleoside compound such as a substituted purine or 7-deazapurine.

Additionally, the compounds of the present invention, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include hemihydrates, monohydrates, dihydrates, trihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O. A hemihydrate is formed by the combination of one molecule of water with more than one molecule of the substance in which the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

As defined herein, the term “derivative” refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by Formula (I) are substituted purine compounds or substituted 7-deazapurine compounds, and have Formula (I) as a common core.

The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

The present invention provides methods for the synthesis of the compounds of any of the Formulae disclosed herein. The present invention also provides detailed methods for the synthesis of various disclosed compounds of the present invention according to the schemes and the Examples described in WO2012/075381, WO2012/075492, WO2012/082436, and WO2012/75500, the contents of which are hereby incorporated by reference in their entireties.

Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present invention are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present invention.

In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the invention to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers.

Compounds described herein are assayed for modulation of activity, for example, histone methylation, modulation of cell growth and/or IC₅₀, described in the examples below. IC₅₀ values are presented as A=<0.1 μM; B=>0.1 μM and <1 μM; C=>1 μM and <10 μM; and D=>10 μM and <50 μM.

Compound DOT1L IC₅₀ (μM) A2 0.00074 A3 0.00073 A5 0.00059 A69 0.00251 A75 0.00059 A86 0.00062 A87 0.0008 A91 0.00218 A93 0.00292

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

EXAMPLES Assays of Enzymatic Activity

Unless otherwise indicated, assays of DOT1L enzymatic activity were performed under balanced conditions (all substrates present at concentrations equal to their respective K_(M) values) using a radiometric assay of S-[methyl-³H]adenosyl-L-methionine transfer from SAM to chicken erythrocyte nucleosomes as previously described. Reactions were initiated by addition of S-[methyl-³H]adenosyl-L-methionine and allowed to run at room temperature for 120 minutes before being quenched by the addition of 800 μM cold SAM.

Compound IC₅₀ values were determined from assays of enzymatic activity in which compound was titrated into reaction mixtures by 3-fold serial dilution from DMSO stocks. For each titration, 10 concentrations of inhibitor were used along with 100% inhibition (2.5 μM SAH) and 0% inhibition (1 μL of neat DMSO per well) controls. Plots of residual enzyme velocity as a function of inhibitor concentration were fit to a standard Langmuir isotherm equation (12) to derive estimates of the IC₅₀ value of the compound. As described herein, the inhibition modality of key compounds within the aminonucleoside series were tested and always found to be competitive with SAM and noncompetitive with respect to nucleosome substrate. For most compounds, the K_(i) value was calculated from the IC₅₀ value using the appropriate equation for competitive inhibition with respect to SAM.

For selected compounds, the inhibition modality with respect to the two substrates (SAM and nucleosomes) were determined by dual titration of compound and varied substrate concentration while holding the other substrate fixed at its K_(M) value. Plots of velocity as a function of varied substrate at multiple inhibitor concentrations were globally fit to a general equation for enzyme inhibition using Graphpad Prism. Selection of the modality for each data set was done by evaluating the value of α, a term related to the degree of cooperative or anticooperative interaction between substrate and inhibitor binding, as previously described. A value of α≧10 was taken as consistent with competitive inhibition, while a value of α≦0.1 was taken as consistent with uncompetitive inhibition. Values of α between 10 and 0.1 were considered to be consistent with noncompetitive inhibition.

Compounds that displayed an IC₅₀ value within 50-fold of the enzyme concentration used in initial assays ([E]=0.25 nM) were treated as tight binding inhibitors. In this case, the K_(i) value was determined by measuring the IC₅₀ value of the compound (vide supra) at varying concentrations of enzyme from 5 nM to 0.25 nM. A plot of IC₅₀ as a function of enzyme concentration was fit to a linear equation and the y-intercept value was equivalent to K_(i)(1+[S]/K_(M)) where [S] and K_(M) refer to SAM, the substrate with which these inhibitors compete. Knowing the values of [S] and K_(M) used in the assay, the K_(i) value was then calculated from the y-intercept value.

Determination of Ligand Association and Dissociation Rate Constants

Ligand association and dissociation rate constants were determined by surface plasmon resonance (SPR). DOT1L was stored in 20 mM Tris-HCl, 200 mM NaCl, 1 mM EDTA, 1 mM DTT, pH 7.8 and immobilized by direct amine coupling, diluting enzyme into coupling buffer containing 10 mM Hepes pH 7.4, 1 mM TCEP. Immobilization run buffer contained 10 mM Hepes pH 7.4, 150 mM NaCl, 500 μM TCEP, and approximately 10,000 RUs (response units) of DOT1L was captured. A reference channel of a surface that was activated in parallel and blocked was created in a second flow cell was also created. Data was captured on either a Biacore 4000 (chip CM5) or a Biorad ProteOn (chip GLM).

K_(d) determinations were determined using run buffer containing 20 mM Tris pH 8.0, 10 mM NaCl, 100 mM KCl, 0.002% Tween-20, 500 μM TCEP, 2% DMSO, with the following injection parameters: 30 μl/min flow rate, with a 30 second association phase followed by monitoring dissociation for 30 seconds. Experiments were carried out at 25° C.

Cell Proliferation Assay

The human leukemia cell line MV4-11 harboring the MLL-AF4 translocation was obtained from ATCC (CRL-9591). Cells were grown in Iscove's Modified Dulbecco's Medium (IMDM) with 10% Fetal Bovine Serum (FBS). All cell culture reagents were purchased from Invitrogen Life Technologies and cells were maintained in a humidified incubator set to 37° C., 5% CO₂.

Cell proliferation was assessed by plating, in triplicate, exponentially growing MV4-11 cells in a 96 well plate at a density of 3×10⁴ cells/well in a final volume of 150 μL. Cells were incubated in the presence of compound at increasing concentrations up to 50 μM. Viable cell numbers were determined every 3-4 days for a total of 14 days using the Guava Viacount assay (Millipore #4000-0040). Analysis was performed on a Guava EasyCyte Plus instrument (Millipore) according to the manufacturer's protocol. On days of cell counts, growth media and compound were replaced and cells split back to a density of 5×10⁴ cells/well. Total cell number is expressed as split-adjusted viable cells per well. IC₅₀ values were determined from concentration dependent curves at day 14 using the Graphpad Prism software.

H3K79me2 Quantitative ELISA

Exponentially growing MV4-11 cells were seeded in a 12-well plate at 2×10⁵ cells/well in a final volume of 2 mls. Cells were incubated in the presence of increasing concentrations of Compound C94, C118, or D16 up to 50 μM. Control cells were treated with 0.2% DMSO control. Cells (1-2×10⁶) were harvested after 96 hours of compound incubation and histones were extracted. An indirect enzyme-linked immunosorbent assay (ELISA) using acid extracted histones was run using matching microtiter plates (Immulon 4HBX #3855, Thermo Labsystems). Plates were coated for total H3 and H3K79me2 detection with either 75 ng or 1500 ng/well of histones respectively. The coating antigen was diluted in coating buffer (PBS+0.05% BSA) for a final volume of 100 μl and allowed to incubate overnight. The plates were blocked with 300 μl blocking buffer (PBST+2% BSA) for 2 hours at RT, followed by a 2 hour incubation with 100 μl primary antibody (1:750 H3K79me2, CST 5472; or 1:5000 total H3, Abcam ab1791) diluted in blocking buffer at RT. 100 μl of HRP tagged goat-anti-rabbit antibody (1:4000, CST 7074) in blocking buffer was added and allowed to incubate for 2 hours at RT. The reaction was visualized with 100 μl 3,3′,5,5′ tetramethylbenzidine substrate (TMBS, BioFx Laboratories) and stopped with an equivalent volume of 1 N sulfuric acid. Plates were read at 450 nm on an M5e plate spectrophotometer. Following each step, plates were washed 3 times with wash buffer (PBST), with an additional wash included following secondary antibody.

Quantitative Real-Time PCR Analysis

Exponentially growing MV4-11 cells were plated in a 12 well plate at 2×10⁵ cells/well in a final volume of 2 mL. Cells were incubated with increasing concentration of test compounds (e.g., Compounds C94, C118, and D16 up to 50 μM for 6 days. Compound and media were refreshed on day 4 and cells split back to 5×10⁵ cells/well. Cells were pelleted and processed as previously described.

Example 1 Structure Determination of DOT1L with Compound

The production of His-DOT1L-1-416 (SEQ ID NO: 1) and crystallization with SAM have been reported previously. Compound C1 was pre-incubated with DOT1L-1-416 (SEQ ID NO: 1) in 10 fold molar excess and then co-crystallization was set up with the hanging drop method using solution containing 100 mM sodium acetate, 1.8-2.0 M ammonium sulfate, 5 mM Tris(2-carboxyethyl)phosphine (TCEP), pH 5.5, at 20 OC. In order to observe the protein at a physiological pH, crystals were transferred using nylon loops into a pH 7.5 Tris buffer (100 mM Tris-HCl (pH 7.5), 2.0 M ammonium sulfate, 5 mM TCEP). This transfer was done stepwise by soaking the crystals over the course of one hour in successive mixtures of acetate and Tris buffers. The crystals were equilibrated in the final Tris buffer at pH 7.5 overnight at 20° C. The crystal were next transferred stepwise into cryoprotectant (25 mM Tris-HCl, 2.0 M ammonium sulfate, 30% glycerol, pH 7.5), and flash-frozen in liquid nitrogen. Data collection was done at beamline X12B at the National Synchrotron Light Source at Brookhaven National Labs, Upton, N.Y.

For Compounds C118 and D16, DOT1L bound structures were obtained by the soaking method. The DOT1L-SAM crystals were cross-linked by exposing the crystal containing hanging drop over the vapor of 1 μl of 25% glutaraldehyde, pH 3.0, for 1 hr (13, 14) and then soaked with mother liquor containing 1 mM compound overnight. The crystals were cryo-protected with 35% glucose in mother liquor and flash-frozen in liquid nitrogen. The diffraction data sets were collected at beamline 17U at the Shanghai Synchrotron Radiation Facility. All data were processed by HKL2000. Structures were solved by molecular replacement (Phaser) using the DOT1L-SAM structure (PDB code:3QOW) with the SAM molecule removed as a search model. Refinement was carried out by Refmac5 and the model building was carried out by COOT. Detailed information of the diffraction data, refinement, and structure statistics are provided in Table 7 below. The 2fo-fc maps for the three ligands are shown in FIG. 10A-C. The coordinates for the crystal structures have been deposited with PDB code of 4EK9 (DOT1L-Compound C1), 4EKG (DOT1L-Compound C118) and 4EKI (DOT1L-Compound D16). Structural coordinates for DOTDOT L-Compound D16 and DOT1L-Compound A2 are respectively provided in Tables S1 and S2 in the Appendix.

Example 2 Designing DOT1L Inhibitors Mechanism-Guided Design Tenets

In the case of DOT1L, methyl transfer from the thiomethyl moiety of SAM to the ε-N of the bound side chain of lysine 79 of histone H3 (H3K79) proceeds through a simple S_(N)2 mechanism, requiring stringent alignment of the molecular orbitals of the methyl donor and acceptor atoms. The crystal structures of DOT1L bound to SAM and to the reaction product SAH illustrate a highly ordered active site with superimposable SAM and SAH configurations in the bound structure. The thiomethyl group of SAM is directed into a contiguous channel that forms the lysine binding pocket of the enzyme, thus facilitating facile group transfer once the ternary enzyme-SAM-histone complex has formed. Steady state kinetic analysis suggests that DOT1L functions by a distributive mechanism, requiring dissociation of the enzyme from the histone substrate after each round of lysine 79 methylation. The product SAH binds to DOT1L with relatively high affinity (K_(i)=320 nM), suggesting that product dissociation may be at least partially rate-limiting to enzyme turnover.

In one aspect of the invention, the above biochemical data provided a starting point for inhibitor design. The drug design started based on the structure of the reaction product SAH, with the following key objectives. First objective was to reduce the polar surface area of the ligand by replacement of charged and/or polar functionalities. Second objective was to engage recognition elements within both the SAM/SAH binding pocket and the adjacent lysine binding pocket to gain the affinity advantages of bisubstrate inhibitors. Lastly, these two goals should be accomplished while reasonable ligand efficiency is maintained and/or the pharmacological tractability of the compound series is improved.

The initial approach towards the above stated objectives was to replace the highly polarizable sulfur atom, eliminate the charged groups on the amino acid portion of SAH, and minimize the molecular mass contributed to by the amino acid side chain. To this end, the homocysteine moiety of SAH was replaced with a simple dimethyl amine to create a minimal pharmacophore, as represented by Compound C1. Despite these significant changes, Compound C1 retained a reasonable degree of binding affinity for DOT1L (K_(i)=38 μM); the binding free energy change (ΔΔG_(binding)) for this compound, relative to SAH, was only 2.9 kcal/mol (at 25° C.). Additionally, crystallographic analysis of the binary complex of DOT1L and Compound C1 confirmed that, despite the S to N substitution, the compound binds within the active site of the enzyme in the same configuration as SAM. These data establish the utility of Compound C1 as a founder molecule for SAR (structure-activity relationship) elaboration.

Structure-Activity Relationships for SAH Mimetic DOT1L Inhibitors

The modification of Compound C1 by independent alterations to the alkyl side chains appended to the nitrogen atom of the 5′ amine. Fixing one substituent as methyl, the second substituent was systematically varied with low molecular weight substituents with more effectively engaging recognition elements near the juxtaposition of the SAM and lysine binding pockets. To this end, a library of 25 compounds were prepared and tested for DOT1L inhibition. From this library the Compound C2 was identified, which demonstrated a DOT1L K_(i) of 12 μM.

The isopropyl group of Compound C2 was speculated to reach into the lysine binding pocket. Based on this assumption, this functionality was further developed to further engage elements within this channel and simultaneously engage recognition elements within the amino acid binding pocket by varying the substituent. In the course of library building for these purposes, key intermediate species along the synthetic route were tested. The FMoc-protected intermediate Compound C64 displayed potency for inhibition of DOT1L, with a K_(i) of 20 μM. The instability of this compound precluded detailed structural characterization by crystallography. This finding did, however, lead to replacing the functionality with a short tether, linked to a large hydrophobic group. Replacing the FMoc group with a tert-butyl phenyl urea resulted in Compound C94, which showed a marked improvement in potency (K_(i)=845 nM). Combining this replacement with an extension of the tether group by one methylene (from ethyl to propyl) led to even greater target engagement, as exemplified by Compound C118, a compound with a K_(i) of 13 nM.

In one aspect of the invention, tolerance of DOT1L inhibitors for substitutions within the nucleoside portion of the pharmacophore was determined. In general, substitutions on the nucleoside were not well tolerated. However, the ring nitrogen at position 7 could be substituted by carbon; the resulting deazapurine compounds demonstrated potent inhibition of DOT1L as exemplified by compound D8, an inhibitor displaying a K_(i) of 4 nM.

Combining the 7 deazapurine moiety with the tert-butyl phenyl urea and 5′-amino isopropyl groups (vide supra) yielded compound D16. As previously described, D16 is a potent (K_(i)=300 μM), selective inhibitor of DOT1L that demonstrates activity in inhibiting intracellular methylation of H3K79 and selective killing of MLL-rearranged leukemia cell lines. This compound also demonstrated a statistically significant survival advantage in an aggressive, disseminated mouse model of MLL-rearranged leukemia.

Conformational Adaptation Drives Inhibitor Potency and Long Residence Time

Conformational adaptation appears to play a critical role in driving inhibitor potency among the aminonucleoside inhibitors of DOT1L.

Table 5 below summarizes the kinetics of inhibitor association and dissociation with DOT1L for the enzymatic product SAH and for three key compounds (Compounds C94, C118 and D16), as measured by surface plasmon resonance.

TABLE 5 K_(i) K_(d) k_(on) k_(off) Compound (nM) (nM) ^(a) (M⁻¹s⁻¹) (s⁻¹) τ (s.) SAH 320 ± 104 ^(b) 71 ± 40 1.4 ± 0.5 (×10⁶) 0.1 ± 0.04 10 ± 1 C94 845 ± 472 ^(b) 167 ± 100 1.2 ± 0.8 (×10⁶) 0.2 ± 0.09  5 ± 3 C118 13 ± 7 ^(b)  1.7 ± 0.2 1.20 ± 0.1 (×10⁷)  0.02 ± 0.001 50 ± 3 D16 0.30 ± 0.02 ^(c) 0.10 ± 0.02 3.0 ± 0.4 (×10⁶) 3 ± 0.3 (×10⁻⁴) 3333 ± 300 ^(a) Kd calculated as k_(off)/k_(on). ^(b) Errors represented as standard deviation (SD) ^(c) K_(i) determined from concentration-dependent effects of compound on enzyme activity as described in Materials and Methods; error represented as standard error of measurement (SEM)

First, as noted above, there was a significant jump in target potency between C94 and C118 (ΔΔG_(binding)=2.3-2.5 kcal/mol at 25° C.) and again between C118 and D16 (ΔΔG_(binding)=2.4-2.9 kcal/mol at 25° C.). The enhancement in target potency seen across this series appears to be driven by a reduction in the dissociation rate of the inhibitors from the binary enzyme-inhibitor complex (k_(off)) which results in a dramatic change in the residence time (τ) of the binary complex from 5 seconds to 1 hour in going from C94 to D16; while the dissociation rate constants and residence times change by over three orders of magnitude among these compounds, the association rate constant (k_(on)) is virtually invariant across the pharmacophore series and is several orders of magnitude slower than the calculated diffusion limit. More advanced inhibitors within the aminonucleoside series continue this trend, displaying residence times greater than 24 hours with no attendant change in association rate constant (such as Compound A2).

The relatively slow association rate constants seen for SAH and the aminonucleosides also suggest a conformational gating of compound access to the SAM/SAH binding site. The upper limit of the association rate constant for diffusion-limited small molecule binding to a protein has been estimated to be on the order of 10⁹ M⁻¹s⁻¹. More typically values of the association rate constant for small molecule substrates binding to enzymes are about 10⁷ M⁻¹s⁻¹ and typical values for the residence time of enzyme substrates and products are in the millisecond to second range (23). Thus, even for the natural product of the enzyme, SAH, the rates of association and dissociation are slow relative to other natural ligands of enzymes. The crystal structures of SAM and SAH bound to DOT1L revealed an occluded active site with no clear, unobstructed pathway from bulk solvent to the active site for compound association or dissociation; thus some conformational adaptation must attend enzyme turnover in order for substrate to access the binding pocket and for product to be released.

These data also imply conformational adaptation of the enzyme in response to more potent (e.g., Compounds C118 and D16) inhibitor binding. Two possible conformational mechanisms are consistent with the data presented in Table 5. The first is referred to as a conformational selection mechanism in which the free enzyme exists in two conformational states that are in (slow) equilibrium with one another: a state that binds inhibitor and one that does not. Binding of the inhibitor shifts the equilibrium in favor of the inhibitor-binding conformation. The second mechanism is referred to as the induced-fit mechanism. In this model the inhibitor binds to the enzyme in a non-optimal conformational state and then induces a conformational adjustment of the enzyme to create a more complementary, tighter binding state of the binary enzyme-inhibitor complex. A third mechanism of slow association and slow dissociation results from situations in which the conformation of the enzyme does not change, but other factors limit the rate of ligand binding and dissociation. In this third situation, binding is often gated by the need for slow displacement of structured water molecules within the active site, displacement of metal binding ligands, and similar slow processes that are distinct from conformational adjustments of the protein per se.

The induced-fit mechanism is predominant among enzyme-inhibitor interactions. However the current data do not allow one to definitively distinguish between the two conformational adaptation models described above. In either case, the low-affinity conformational state appears to be kinetically (and thermodynamically) insignificant in terms of inhibitor interactions. This is evident from the excellent agreement between the K_(i) values for the inhibitor series, determined from the concentration dependent effects of compounds on enzyme activity, and the K_(d) values determined from the SPR binding experiments (Table 5). The K_(d) values in Table 5 are calculated simply as the ratio of k_(off) over k_(on), thus assuming a single step binding and dissociation mechanism. If an intervening conformational state were kinetically significant in the inhibitor binding pathway, one would expect to see biphasic association curves in the enzymatic assay or the SPR binding or both. The good agreement between the K_(i) and simply calculated K_(d) values here argues against a significant kinetic role for an intervening conformational state. A similar situation is encountered in other enzyme-inhibitor systems that work through an induced-fit mechanism for which the initial encounter complex is kinetically insignificant and rapidly isomerizes to the final conformational state of the tight-binding enzyme-inhibitor complex.

Structural Changes Attending Inhibitor Binding

The inference drawn from the binding kinetics of conformational adaptation in DOT1L-inhibitor interactions is supported by crystallographic analysis of the structures of DOT1L-inhibitor binary complexes. Steady state kinetic analysis of DOT1L inhibition by the aminonucleosides consistently demonstrated competitive inhibition with respect to SAM and noncompetitive inhibition with respect to nucleosome (as exemplified for Compound D16 in FIG. 2). This kinetic characterization is consistent with the crystallographic data that demonstrates compound binding within the SAM/SAH binding pocket for all tested compounds. As described above, the structures of the founder Compound C1 and SAH are virtually superimposable (FIG. 3). The more potent Compounds C118 and D16 both contain an extended (i.e., propyl) tether and terminal hydrophobic groups appended to the 5′ amino nitrogen. It was initially expected that these extended structures would reach into the proximal lysine binding channel of the enzyme, creating a bisubstrate-like mode of inhibitor interaction. However, the crystal structure of DOT1L-Compound C118 reveals an unanticipated mode of interaction with the enzyme.

The DOT1L-Compound C118 structure reveals that the inhibitor reaches into a heretofore-unrecognized pocket immediately adjacent to the amino acid binding subsite of the SAM/SAH binding pocket of the enzyme (FIG. 4). This pocket—which does not exist in the structures of the enzyme with SAM, SAH or Compound C1—is opened up by the tert-butyl phenyl urea functionality of Compound C118. More specifically, the crystal structure of C118 reveals a number of novel interactions with DOT1L. For example, the charged 5′-amino group of the compound forms a hydrogen bond with the carbonyl oxygen of Gly163. The urea region occupies the binding site of the amino acid region of SAM. The terminal propyl nitrogen of the urea interacts with the side chain oxygen atom of Asp161 in the same binding mode as the carboxylate nitrogen atom in SAM. The urea carbonyl oxygen interacts with the nitrogen atom of Asn241, similar to the interaction of one of the carboxylate oxygen atoms of SAM. In addition, the proximal nitrogen atom of the urea (attached to the aromatic ring) coordinates with Asp161 (FIG. 4A). The steric bulk of the tert-butyl phenyl opens up the novel hydrophobic pocket by changing the side chain conformation of Phe239, Tyr312, Met147 and Leu143, inducing a significant conformational change in the 130s' loop to flip Thr139 (a residue that otherwise interacts with the carboxylate terminus of SAM) away from the SAM binding pocket (FIG. 4B). The movement of Tyr312 causes a change in a loop consisting of residues 302-312 (300s' loop). These changes result in both the 130s' and 300s' loops of DOT1L becoming disordered (FIG. 4C).

The crystal structure of the DOT1L-D16 complex reveals D16 binds to DOT1L in a similar manner as C118, with the 5′-amino isopropyl group occupying a region near that occupied by the methyl group of the thiomethyl on SAM (FIG. 5). Thus, the high potency, longer residence time compounds C118 and D16 are associated with a novel conformation of the enzyme that expands the contiguous active site cavity to include a new pocket; the crystal structures of these compounds suggest that these inhibitors “punch through” a protein wall to create this new pocket and to thus engage recognition elements both within the SAM/SAH binding pocket and the newly formed hydrophobic pocket. Because this conformational change is unique to DOT1L, these compounds show excellent selectivity against other PMTs (9).

In addition to the protein structural changes that attend potent inhibitor binding, it is often the case that inhibitor-induced displacement of key structural water molecules within enzyme active sites is a critical component of high-affinity ligand interactions. This may be a contributing factor in the tight-binding interactions between DOT1L and the aminonucleoside inhibitors presented here. However, the resolution of the various enzyme-inhibitor co-crystal structures is not sufficient for us to make any definitive statements with regard to the role of structural water molecule displacement in the binding of these compounds to DOT1L.

Correlation of Enzyme-Inhibitor Affinity with Cellular Activity

Inhibition of DOT1L is expected to lead to a concentration-dependent diminution of H3K79 methylation levels in treated cells. For cells bearing the chromosomal translocation of the MLL gene, the diminution of H3K79 methylation is expected to translated into reduced transcription of leukemogenic genes such as HOXA9(27) and thus to a concomitant inhibition of cell proliferation. It was demonstrated that the potent, selective DOT1L inhibitor D16 indeed leads to concentration-dependent inhibition of intracellular H3K79 dimethylation (H3K79me2), of HOXA9 gene transcription and antiproliferative effects selectively for MLL-rearranged leukemia cells. Hence, there appears to be a correlative relationship between DOT1L target engagement, reduction in intracellular formation of the enzyme product (H3K79me2) and downstream transcriptional events leading to antiproliferative efficacy for D16. In this study, these observations were extended to other members of the aminonucleoside series to establish more firmly the relationship between target engagement and phenotypic effects of DOT1L inhibitors.

Compounds C94, C118 and D16 provide a structurally related series of DOT1L inhibitors, spanning almost 4 orders of magnitude in target affinity, with which to test the relationship between enzyme inhibition and cellular efficacy. Various concentrations of each of these compounds were applied to MV4-11 cells bearing a chromosomal rearrangement of the MLL gene and the impact on H3K79me2 level, HOXA9 message and cell proliferation were assessed at appropriate time points, taking into account the distinct kinetics of compound impact on each of these cellular parameters. Table 6 below summarizes the results of these studies.

TABLE 6 Cellular IC₅₀ μM Com- H3K79 HOXA9 pound K_(i) (nM) Methylation mRNA Proliferation C94 845 ± 472 28 ± 25 >50 >50 C118 13 ± 7  0.272 ± 0.014 6.9 ± 0.5 4.9 ± 3.9 D16 0.30 ± 0.02 0.005 ± 0.003 0.83 ± 0.17 0.146 ± 0.072 Errors represented as standard deviation (SD)

Consistent with our mechanistic hypothesis, the data in Table 6 illustrate a clear relationship between enzyme engagement, inhibition of intracellular histone methylation, selective effects on gene transcription and antiproliferative efficacy. As was previously reported for D16, each of these DOT1L inhibitors showed selective inhibition of intracellular H3K79 methylation without effect on other histone methyl marks. Further, the antiproliferative effects of each of these DOT1L inhibitors were specific to MLL-rearranged leukemia cell lines; other leukemia cell lines without the chromosomal rearrangement of the MLL gene were essentially unaffected (antiproliferative IC₅₀>50 μM) by this series of DOT1L inhibitors. These data provide compelling evidence for a causal relationship between DOT1L inhibition and selective cell killing of MLL-rearranged leukemia cells by the aminonucleoside compound series.

The potent and selective inhibition of DOT1L by the aminonucleoside series translates into potent and selective inhibition of intracellular H3K79 methylation and to selective cell killing for leukemic cells bearing the MLL chromosomal translocation. The quantitative correlation between target engagement, intracellular inhibition of H3K79 methylation, and antiproliferative effects is striking, and leaves little doubt that the selective phenotypic effects of these compounds are driven directly by ablation of DOT1L enzymatic activity. These data provide a solid foundation upon which further optimization of DOT1L inhibitors may be conducted. The data provide compelling proof of concept for the application of DOT1L inhibitors for selective killing of MLL-rearranged leukemias and thus portent the utility of DOT1L inhibitors for therapeutic intervention in this disease.

Example 3 Tumor Anti-Proliferation Assays

The enzymatic activity of the protein methyltransferase (PMT) DOT1L has been shown to be a driver of cell proliferation in MLL-rearranged leukemia. Structure-guided design, together with robust biochemical and biological assays, was used to optimize the potency, selectivity and pharmacological features of the aminonucleosides, resulting in the Compound A2.

Compound A2 is a S-adenosyl methionine (SAM) competitive inhibitor of DOT11L that displays a K_(i) value of 80 μM and a drug-target residence time of >24 hours. The compound is highly selective for DOT1L, demonstrating >37,000-fold selectivity against all other PMTs tested. Crystallographic studies reveal that the high affinity, durable inhibition of DOT1L by Compound A2 has its origin in a conformational adaptation of the protein that attends inhibitor binding, extending the compound binding pocket to include novel recognition elements beyond the SAM binding active site, as illustrated in FIG. 6. Treatment of leukemia cells with Compound A2 results in concentration- and time-dependent diminution of H3K79 methylation without effect on the methylation status of other histone sites. The diminution of H3K79 methylation leads to inhibition of key MLL target genes and selective, apoptotic cell killing in MLL-rearranged leukemia cells, but has minimal impact on non-rearranged cells. Compound A2 is highly soluble in aqueous solution and can thus be formulated for intravenous administration. The effective pharmacokinetic half-life of Compound A2 in systemic circulation has been measured to be 0.25 and 1.5 h in rats and dogs, respectively. A nude rat subcutaneous xenograft model of MLL-rearranged leukemia has been established.

Four groups of 10 (Groups 1, 2, 3, and 4 female RH nu/nu rats (7 weeks old, weighing 120-160 g) bearing MV4-11 xenograft tumors of sizes ranging from 300-600 mm³ were implanted with a catheter in the femoral vein). The infusion flow rate was set at 1,500 μL/hour/kg and was adjusted to the most recent mean body weight of each treatment group (as an example, the infusion flow rate was 300 μL/hour for a group of rats having a mean body weight of 200 g). Group 1 received vehicle via a 21-day continuous IV infusion. Group 2 received 21-day continuous IV infusion of the test substance at 35 mg/kg/day. Group 3 received a daily 8-hour continuous IV infusion of the test substance at 67 mg/kg/day for 21 consecutive days. Between two IV infusions of the test substance, the rats were kept under IV infusion with NaCl 0.9% solution. Group 4 received a 21-day continuous IV infusion of the test substance at 70 mg/kg/day. Syringes used for the IV infusion were replaced every day.

Blood samples were taken from all animals in Groups 1, 2, and 4 on designated days and assayed for plasma levels of Compound A2. Tumor size was measured on the designated days as shown in FIG. 1. The rats were terminated when the subcutaneous tumor reached a maximum volume of 9,000 mm³ or at a maximum of 55 days after tumor cells injection.

As shown in FIG. 1, continuous intravenous infusion of Compound A2 for 21 days in this model leads to dose-dependent anti-tumor activity. At the highest dose, complete tumor regressions are achieved with no regrowth for up to 32 days after the cessation of treatment. In FIG. 1, Dose 1=35 mg/kg/day, and Dose 2=70 mg/kg/day.

No significant weight loss or obvious toxicity was observed in rats treated with Compound A2 during this efficacy study. Compound A2 is thus a potent, selective inhibitor of DOT1L that demonstrates strong efficacy in a rat xenograft model of MLL-rearranged leukemia.

TABLE 7 Summary of the Diffraction Data, Refinement, and Structure Statistics for Crystal Structures Compound C1 Compound C118 Compound D16 Diffraction Data Resolution (Å)* 25.00-2.50 (2.59-2.50)

1.70-2.80 (2.95-2.80) 50.00-2.85 (2.95-2.85) Space group P65 P65 P65 Unit-cell parameters a (Å) 152.81 157.60 155.05 b (Å) 152.81 157.60 155.05 c (Å) 51.37 49.15 48.45 α (°) 90.00 90.00 90 β (°) 90.00 90.00 90 γ (°) 120.00 120.00 90 Completemess (%)* 96.7 (81.3) 100.0 (99.9) 99.8 (100.0) Redundancy* 11.5 (3.1) 6.1 (5.9) 5.6 (5.6) Average I/σI* 20.5 (2.41) 11.8 (3.5) 23.1 (4.0) R_(merge) (%)* 9.5 (39.0) 9.4 (42.1) 8.0 (53.9) Refinement Statistics Data (no cutoff) (Å)* 23.94-2.50 (2.56-2.50)

0.00-2.80 (2.87-2.80) 41.09-2.85 (2.92-2.85) R_(working) (%)/No. of reflections* 20.8/20874 (40.0/1274) 21.0/15726 (30.0/1149) 20.9/14244 (27.0/974) R_(free) (%)/No. of reflections* 26.3/1189 (37.8/58) 26.1/886 (40.2/54) 26.2/785 (40.6/61) R.m.s.d in bond lengths (Å) 0.01 0.009 0.009 R.m.s.d in bond angles (°) 1.334 1.291 1.46 Mean B factors (Å²) 58.98 74.06 90.38 Mean B factors for ligand (Å²) 44.47 61.82 75.23 Ramachandran plot Favored (%) 90.3 87.2 87.5 Additionally allowed (%) 9.7 12.8 12.5 Generously allowed (%) 0 0 0 *Values in parentheses are for the highest-resolution shell

indicates data missing or illegible when filed

The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

APPENDIX

TABLE S1 TITLE  CRYSTAL STRUCTURE OF DOT1L IN COMPLEX WITH EPZ004777 CRYST1 155.053 155.053  48.452  90.00 90.00 120.00 P 65      6 ORIGX1    1.000000  0.000000  0.000000     0.00000 ORIGX2    0.000000  1.000000  0.000000     0.00000 ORIGX3    0.000000  0.000000  1.000000     0.00000 SCALE1    0.006449  0.003724  0.000000     0.00000 SCALE2    0.000000  0.007447  0.000000     0.00000 SCALE3    0.000000  0.000000  0.020639     0.00000 ATOM 1 N LYS A 4 11.559 73.167 16.864 1.00 122.46 N ATOM 2 CA LYS A 4 11.526 74.573 16.363 1.00 123.45 C ATOM 3 C LYS A 4 11.676 74.613 14.840 1.00 120.69 C ATOM 4 O LYS A 4 11.076 73.796 14.130 1.00 118.19 O ATOM 5 CB LYS A 4 12.609 75.407 17.039 1.00 121.78 C ATOM 6 N LEU A 5 12.469 75.570 14.357 1.00 110.48 N ATOM 7 CA LEU A 5 12.773 75.726 12.933 1.00 107.29 C ATOM 8 C LEU A 5 13.516 74.517 12.321 1.00 103.99 C ATOM 9 O LEU A 5 14.355 73.895 12.979 1.00 109.08 O ATOM 10 CB LEU A 5 13.559 77.023 12.726 1.00 105.89 C ATOM 11 CG LEU A 5 12.755 78.283 12.343 1.00 107.16 C ATOM 12 CD1 LEU A 5 11.305 78.230 12.811 1.00 96.94 C ATOM 13 CD2 LEU A 5 13.442 79.576 12.785 1.00 92.46 C ATOM 14 N GLU A 6 13.186 74.189 11.070 1.00 90.61 N ATOM 15 CA GLU A 6 13.716 73.000 10.375 1.00 83.94 C ATOM 16 C GLU A 6 13.901 73.228 8.876 1.00 90.90 C ATOM 17 O GLU A 6 13.280 74.123 8.284 1.00 93.50 O ATOM 18 CB GLU A 6 12.785 71.798 10.537 1.00 71.55 C ATOM 19 CG GLU A 6 12.892 71.058 11.854 1.00 76.84 C ATOM 20 CD GLU A 6 12.192 69.698 11.823 1.00 86.30 C ATOM 21 OE1 GLU A 6 12.448 68.900 12.754 1.00 87.72 O ATOM 22 OE2 GLU A 6 11.397 69.407 10.881 1.00 79.35 O ATOM 23 N LEU A 7 14.766 72.420 8.266 1.00 87.34 N ATOM 24 CA LEU A 7 14.727 72.216 6.816 1.00 81.97 C ATOM 25 C LEU A 7 14.592 70.711 6.568 1.00 77.11 C ATOM 26 O LEU A 7 15.086 69.898 7.362 1.00 75.10 O ATOM 27 CB LEU A 7 15.944 72.830 6.118 1.00 77.48 C ATOM 28 CG LEU A 7 16.065 74.364 6.193 1.00 82.84 C ATOM 29 CD1 LEU A 7 17.517 74.800 6.370 1.00 74.92 C ATOM 30 CD2 LEU A 7 15.429 75.084 5.002 1.00 81.08 C ATOM 31 N ARG A 8 13.875 70.332 5.513 1.00 72.20 N ATOM 32 CA ARG A 8 13.720 68.904 5.199 1.00 79.52 C ATOM 33 C ARG A 8 13.992 68.659 3.729 1.00 84.44 C ATOM 34 O ARG A 8 13.578 69.450 2.862 1.00 87.68 O ATOM 35 CB ARG A 8 12.331 68.363 5.544 1.00 78.70 C ATOM 36 CG ARG A 8 11.708 68.936 6.801 1.00 96.63 C ATOM 37 CD ARG A 8 10.194 68.764 6.789 1.00 100.99 C ATOM 38 NE ARG A 8 9.827 67.358 6.952 1.00 104.07 N ATOM 39 CZ ARG A 8 9.876 66.706 8.112 1.00 101.52 C ATOM 40 NH1 ARG A 8 10.279 67.337 9.220 1.00 92.27 N ATOM 41 NH2 ARG A 8 9.528 65.420 8.164 1.00 93.27 N ATOM 42 N LEU A 9 14.700 67.569 3.445 1.00 79.34 N ATOM 43 CA LEU A 9 14.893 67.177 2.061 1.00 77.44 C ATOM 44 C LEU A 9 14.243 65.831 1.805 1.00 73.97 C ATOM 45 O LEU A 9 14.486 64.862 2.533 1.00 66.03 O ATOM 46 CB LEU A 9 16.377 67.160 1.695 1.00 79.05 C ATOM 47 CG LEU A 9 17.170 68.464 1.637 1.00 74.03 C ATOM 48 CD1 LEU A 9 18.539 68.155 1.059 1.00 81.81 C ATOM 49 CD2 LEU A 9 16.481 69.527 0.793 1.00 77.52 C ATOM 50 N LYS A 10 13.399 65.798 0.781 1.00 67.19 N ATOM 51 CA LYS A 10 12.726 64.588 0.389 1.00 73.14 C ATOM 52 C LYS A 10 13.687 63.759 −0.435 1.00 69.65 C ATOM 53 O LYS A 10 14.380 64.293 −1.299 1.00 71.70 O ATOM 54 CB LYS A 10 11.477 64.915 −0.443 1.00 85.23 C ATOM 55 CG LYS A 10 10.209 65.111 0.380 1.00 95.23 C ATOM 56 CD LYS A 10 8.984 65.374 −0.489 1.00 96.06 C ATOM 57 CE LYS A 10 7.707 65.234 0.327 1.00 95.75 C ATOM 58 NZ LYS A 10 6.514 65.146 −0.551 1.00 90.22 N ATOM 59 N SER A 11 13.718 62.457 −0.162 1.00 69.88 N ATOM 60 CA SER A 11 14.516 61.499 −0.929 1.00 67.74 C ATOM 61 C SER A 11 13.957 61.399 −2.323 1.00 71.29 C ATOM 62 O SER A 11 12.751 61.474 −2.495 1.00 79.64 O ATOM 63 CB SER A 11 14.487 60.118 −0.275 1.00 67.19 C ATOM 64 OG SER A 11 14.472 59.109 −1.276 1.00 73.16 O ATOM 65 N PRO A 12 14.824 61.233 −3.335 1.00 81.41 N ATOM 66 CA PRO A 12 14.270 61.096 −4.687 1.00 75.72 C ATOM 67 C PRO A 12 13.647 59.726 −4.912 1.00 68.44 C ATOM 68 O PRO A 12 13.152 59.445 −5.994 1.00 74.54 O ATOM 69 CB PRO A 12 15.501 61.288 −5.590 1.00 71.93 C ATOM 70 CG PRO A 12 16.656 60.875 −4.736 1.00 70.99 C ATOM 71 CD PRO A 12 16.293 61.365 −3.359 1.00 77.59 C ATOM 72 N VAL A 13 13.687 58.857 −3.918 1.00 66.66 N ATOM 73 CA VAL A 13 13.053 57.548 −4.096 1.00 74.16 C ATOM 74 C VAL A 13 12.102 57.197 −2.939 1.00 80.07 C ATOM 75 O VAL A 13 11.876 56.021 −2.623 1.00 84.87 O ATOM 76 CB VAL A 13 14.084 56.425 −4.400 1.00 68.30 C ATOM 77 CG1 VAL A 13 14.809 56.730 −5.695 1.00 57.60 C ATOM 78 CG2 VAL A 13 15.077 56.245 −3.256 1.00 64.65 C ATOM 79 N GLY A 14 11.557 58.237 −2.315 1.00 73.70 N ATOM 80 CA GLY A 14 10.546 58.087 −1.287 1.00 77.34 C ATOM 81 C GLY A 14 10.996 57.506 0.035 1.00 77.29 C ATOM 82 O GLY A 14 10.179 57.001 0.799 1.00 89.95 O ATOM 83 N ALA A 15 12.287 57.570 0.324 1.00 78.96 N ATOM 84 CA ALA A 15 12.765 57.156 1.638 1.00 76.62 C ATOM 85 C ALA A 15 12.453 58.274 2.624 1.00 74.68 C ATOM 86 O ALA A 15 12.060 59.376 2.210 1.00 79.35 O ATOM 87 CB ALA A 15 14.253 56.865 1.595 1.00 72.42 C ATOM 88 N GLU A 16 12.628 58.007 3.917 1.00 69.70 N ATOM 89 CA GLU A 16 12.357 59.031 4.930 1.00 78.77 C ATOM 90 C GLU A 16 13.112 60.329 4.600 1.00 77.36 C ATOM 91 O GLU A 16 14.304 60.295 4.324 1.00 85.69 O ATOM 92 CB GLU A 16 12.686 58.508 6.336 1.00 83.56 C ATOM 93 CG GLU A 16 12.219 57.071 6.602 1.00 89.72 C ATOM 94 CD GLU A 16 10.715 56.877 6.397 0.50 89.31 C ATOM 95 OE1 GLU A 16 10.314 55.876 5.760 0.50 85.58 O ATOM 96 OE2 GLU A 16 9.929 57.733 6.860 0.50 88.97 O ATOM 97 N PRO A 17 12.415 61.476 4.584 1.00 83.00 N ATOM 98 CA PRO A 17 13.119 62.719 4.263 1.00 81.80 C ATOM 99 C PRO A 17 14.239 62.980 5.251 1.00 78.20 C ATOM 100 O PRO A 17 14.241 62.427 6.350 1.00 76.63 O ATOM 101 CB PRO A 17 12.035 63.793 4.424 1.00 77.75 C ATOM 102 CG PRO A 17 11.094 63.198 5.407 1.00 79.83 C ATOM 103 CD PRO A 17 11.040 61.740 5.032 1.00 79.58 C ATOM 104 N ALA A 18 15.197 63.801 4.849 1.00 82.40 N ATOM 105 CA ALA A 18 16.310 64.127 5.712 1.00 73.01 C ATOM 106 C ALA A 18 15.956 65.429 6.388 1.00 77.58 C ATOM 107 O ALA A 18 15.526 66.391 5.735 1.00 78.01 O ATOM 108 CB ALA A 18 17.590 64.253 4.908 1.00 63.80 C ATOM 109 N VAL A 19 16.128 65.443 7.704 1.00 81.32 N ATOM 110 CA VAL A 19 15.692 66.549 8.541 1.00 82.88 C ATOM 111 C VAL A 19 16.888 67.234 9.225 1.00 80.35 C ATOM 112 O VAL A 19 17.589 66.606 10.009 1.00 79.38 O ATOM 113 CB VAL A 19 14.690 66.050 9.623 1.00 79.17 C ATOM 114 CG1 VAL A 19 14.080 67.224 10.361 1.00 77.31 C ATOM 115 CG2 VAL A 19 13.585 65.195 9.011 1.00 77.94 C ATOM 116 N TYR A 20 17.084 68.522 8.953 1.00 78.22 N ATOM 117 CA TYR A 20 18.121 69.333 9.607 1.00 81.75 C ATOM 118 C TYR A 20 17.576 70.389 10.595 1.00 89.01 C ATOM 119 O TYR A 20 16.591 71.064 10.292 1.00 100.79 O ATOM 120 CB TYR A 20 18.940 70.073 8.539 1.00 85.08 C ATOM 121 CG TYR A 20 19.620 69.171 7.536 1.00 89.38 C ATOM 122 CD1 TYR A 20 18.956 68.745 6.385 1.00 82.61 C ATOM 123 CD2 TYR A 20 20.936 68.734 7.743 1.00 83.99 C ATOM 124 CE1 TYR A 20 19.581 67.903 5.478 1.00 81.71 C ATOM 125 CE2 TYR A 20 21.567 67.900 6.831 1.00 76.12 C ATOM 126 CZ TYR A 20 20.889 67.493 5.704 1.00 76.29 C ATOM 127 OH TYR A 20 21.514 66.671 4.807 1.00 71.44 O ATOM 128 N PRO A 21 18.238 70.571 11.758 1.00 89.31 N ATOM 129 CA PRO A 21 17.917 71.694 12.631 1.00 83.01 C ATOM 130 C PRO A 21 18.389 73.018 12.056 1.00 88.41 C ATOM 131 O PRO A 21 19.400 73.063 11.341 1.00 87.98 O ATOM 132 CB PRO A 21 18.751 71.405 13.873 1.00 81.22 C ATOM 133 CG PRO A 21 19.928 70.673 13.341 1.00 85.34 C ATOM 134 CD PRO A 21 19.316 69.748 12.336 1.00 93.55 C ATOM 135 N TRP A 22 17.664 74.088 12.379 1.00 87.01 N ATOM 136 CA TRP A 22 18.176 75.439 12.193 1.00 82.10 C ATOM 137 C TRP A 22 18.450 76.100 13.530 1.00 90.64 C ATOM 138 O TRP A 22 17.729 75.843 14.489 1.00 94.14 O ATOM 139 CB TRP A 22 17.228 76.256 11.369 1.00 73.52 C ATOM 140 CG TRP A 22 17.798 77.596 11.047 1.00 75.17 C ATOM 141 CD1 TRP A 22 17.853 78.703 11.878 1.00 76.94 C ATOM 142 CD2 TRP A 22 18.443 78.025 9.789 1.00 76.24 C ATOM 143 NE1 TRP A 22 18.459 79.761 11.239 1.00 86.44 N ATOM 144 CE2 TRP A 22 18.839 79.423 9.990 1.00 77.46 C ATOM 145 CE3 TRP A 22 18.717 77.416 8.568 1.00 74.98 C ATOM 146 CZ2 TRP A 22 19.476 80.162 8.998 1.00 78.22 C ATOM 147 CZ3 TRP A 22 19.364 78.172 7.573 1.00 75.79 C ATOM 148 CH2 TRP A 22 19.734 79.512 7.787 1.00 77.10 C ATOM 149 N PRO A 23 19.550 76.887 13.644 1.00 92.30 N ATOM 150 CA PRO A 23 20.591 77.080 12.632 1.00 86.39 C ATOM 151 C PRO A 23 21.282 75.761 12.374 1.00 81.09 C ATOM 152 O PRO A 23 21.382 74.906 13.280 1.00 80.65 O ATOM 153 CB PRO A 23 21.547 78.085 13.276 1.00 88.59 C ATOM 154 CG PRO A 23 21.388 77.861 14.734 1.00 96.33 C ATOM 155 CD PRO A 23 19.941 77.480 14.936 1.00 97.81 C ATOM 156 N LEU A 24 21.702 75.596 11.126 1.00 74.42 N ATOM 157 CA LEU A 24 22.324 74.372 10.660 1.00 69.83 C ATOM 158 C LEU A 24 23.739 74.217 11.232 1.00 71.45 C ATOM 159 O LEU A 24 24.557 75.146 11.134 1.00 62.32 O ATOM 160 CB LEU A 24 22.415 74.430 9.160 1.00 66.08 C ATOM 161 CG LEU A 24 21.135 74.674 8.402 1.00 56.89 C ATOM 162 CD1 LEU A 24 21.557 75.296 7.089 1.00 53.00 C ATOM 163 CD2 LEU A 24 20.455 73.333 8.206 1.00 54.20 C ATOM 164 N PRO A 25 24.036 73.038 11.812 1.00 70.59 N ATOM 165 CA PRO A 25 25.338 72.803 12.442 1.00 71.75 C ATOM 166 C PRO A 25 26.505 73.023 11.493 1.00 70.36 C ATOM 167 O PRO A 25 26.368 72.922 10.258 1.00 68.18 O ATOM 168 CB PRO A 25 25.280 71.321 12.833 1.00 71.82 C ATOM 169 CG PRO A 25 23.827 70.999 12.902 1.00 72.55 C ATOM 170 CD PRO A 25 23.212 71.819 11.804 1.00 68.44 C ATOM 171 N VAL A 26 27.647 73.346 12.075 1.00 69.89 N ATOM 172 CA VAL A 26 28.908 73.277 11.335 1.00 72.95 C ATOM 173 C VAL A 26 29.654 72.047 11.846 1.00 68.76 C ATOM 174 O VAL A 26 29.553 71.699 13.039 1.00 65.86 O ATOM 175 CB VAL A 26 29.739 74.585 11.417 1.00 71.15 C ATOM 176 CG1 VAL A 26 29.277 75.444 12.565 1.00 76.50 C ATOM 177 CG2 VAL A 26 31.219 74.297 11.577 1.00 76.25 C ATOM 178 N TYR A 27 30.350 71.364 10.935 1.00 70.07 N ATOM 179 CA TYR A 27 31.046 70.096 11.266 1.00 72.10 C ATOM 180 C TYR A 27 32.522 70.302 11.658 1.00 73.43 C ATOM 181 O TYR A 27 32.999 69.723 12.642 1.00 69.33 O ATOM 182 CB TYR A 27 30.933 69.109 10.103 1.00 63.02 C ATOM 183 CG TYR A 27 29.505 68.722 9.778 1.00 64.65 C ATOM 184 CD1 TYR A 27 28.684 68.128 10.741 1.00 61.52 C ATOM 185 CD2 TYR A 27 28.967 68.968 8.511 1.00 62.95 C ATOM 186 CE1 TYR A 27 27.390 67.762 10.441 1.00 62.08 C ATOM 187 CE2 TYR A 27 27.667 68.620 8.205 1.00 57.70 C ATOM 188 CZ TYR A 27 26.883 68.018 9.167 1.00 65.81 C ATOM 189 OH TYR A 27 25.576 67.664 8.869 1.00 74.91 O ATOM 190 N ASP A 28 33.199 71.154 10.886 1.00 67.07 N ATOM 191 CA ASP A 28 34.616 71.451 10.988 1.00 69.15 C ATOM 192 C ASP A 28 34.826 72.730 10.178 1.00 73.67 C ATOM 193 O ASP A 28 33.869 73.246 9.578 1.00 73.43 O ATOM 194 CB ASP A 28 35.460 70.303 10.412 1.00 66.90 C ATOM 195 CG ASP A 28 35.355 70.180 8.892 1.00 73.46 C ATOM 196 OD1 ASP A 28 35.442 71.209 8.174 1.00 68.45 O ATOM 197 OD2 ASP A 28 35.213 69.030 8.403 1.00 77.17 O ATOM 198 N LYS A 29 36.062 73.220 10.127 1.00 69.48 N ATOM 199 CA LYS A 29 36.349 74.516 9.514 1.00 72.24 C ATOM 200 C LYS A 29 35.912 74.598 8.053 1.00 75.98 C ATOM 201 O LYS A 29 35.663 75.688 7.555 1.00 86.69 O ATOM 202 CB LYS A 29 37.841 74.875 9.666 1.00 89.07 C ATOM 203 CG LYS A 29 38.201 76.338 9.413 1.00 90.87 C ATOM 204 CD LYS A 29 39.710 76.578 9.397 1.00 99.60 C ATOM 205 CE LYS A 29 40.021 78.069 9.273 1.00 102.22 C ATOM 206 NZ LYS A 29 41.411 78.378 8.826 1.00 105.11 N ATOM 207 N HIS A 30 35.781 73.460 7.374 1.00 80.95 N ATOM 208 CA HIS A 30 35.474 73.462 5.933 1.00 88.17 C ATOM 209 C HIS A 30 34.225 72.700 5.549 1.00 84.97 C ATOM 210 O HIS A 30 34.087 72.293 4.395 1.00 82.53 O ATOM 211 CB HIS A 30 36.667 72.918 5.133 1.00 102.37 C ATOM 212 CG HIS A 30 38.013 73.462 5.577 1.00 110.35 C ATOM 213 ND1 HIS A 30 38.517 74.626 5.111 1.00 107.23 N ATOM 214 CD2 HIS A 30 38.960 72.949 6.471 1.00 109.01 C ATOM 215 CE1 HIS A 30 39.718 74.852 5.683 1.00 118.08 C ATOM 216 NE2 HIS A 30 39.987 73.824 6.514 1.00 119.99 N ATOM 217 N HIS A 31 33.322 72.474 6.506 1.00 79.71 N ATOM 218 CA HIS A 31 32.082 71.721 6.271 1.00 75.39 C ATOM 219 C HIS A 31 31.004 72.081 7.243 1.00 75.51 C ATOM 220 O HIS A 31 31.222 72.069 8.464 1.00 72.11 O ATOM 221 CB HIS A 31 32.319 70.216 6.378 1.00 79.56 C ATOM 222 CG HIS A 31 33.460 69.721 5.534 1.00 87.23 C ATOM 223 ND1 HIS A 31 34.747 69.927 5.868 1.00 84.08 N ATOM 224 CD2 HIS A 31 33.473 69.029 4.334 1.00 82.25 C ATOM 225 CE1 HIS A 31 35.538 69.394 4.934 1.00 87.77 C ATOM 226 NE2 HIS A 31 34.760 68.841 3.997 1.00 81.02 N ATOM 227 N ASP A 32 29.819 72.372 6.718 1.00 70.47 N ATOM 228 CA ASP A 32 28.646 72.583 7.559 1.00 71.27 C ATOM 229 C ASP A 32 27.436 71.965 6.912 1.00 64.40 C ATOM 230 O ASP A 32 27.497 71.562 5.757 1.00 61.62 O ATOM 231 CB ASP A 32 28.405 74.078 7.787 1.00 71.19 C ATOM 232 CG ASP A 32 28.338 74.865 6.501 1.00 73.26 C ATOM 233 OD1 ASP A 32 27.909 74.327 5.465 1.00 79.48 O ATOM 234 OD2 ASP A 32 28.707 76.049 6.526 1.00 83.84 O ATOM 235 N ALA A 33 26.321 71.928 7.635 1.00 67.27 N ATOM 236 CA ALA A 33 25.085 71.374 7.069 1.00 62.24 C ATOM 237 C ALA A 33 24.494 72.212 5.917 1.00 63.41 C ATOM 238 O ALA A 33 23.940 71.661 4.956 1.00 64.01 O ATOM 239 CB ALA A 33 24.072 71.125 8.148 1.00 50.07 C ATOM 240 N ALA A 34 24.627 73.534 5.986 1.00 61.47 N ATOM 241 CA ALA A 34 24.161 74.355 4.878 1.00 61.33 C ATOM 242 C ALA A 34 24.654 73.767 3.571 1.00 67.56 C ATOM 243 O ALA A 34 23.849 73.473 2.661 1.00 73.17 O ATOM 244 CB ALA A 34 24.630 75.787 5.014 1.00 58.78 C ATOM 245 N HIS A 35 25.971 73.568 3.479 1.00 69.69 N ATOM 246 CA HIS A 35 26.568 73.129 2.213 1.00 63.66 C ATOM 247 C HIS A 35 26.293 71.691 1.924 1.00 56.08 C ATOM 248 O HIS A 35 26.099 71.334 0.760 1.00 53.02 O ATOM 249 CB HIS A 35 28.035 73.499 2.113 1.00 71.29 C ATOM 250 CG HIS A 35 28.268 74.992 2.062 1.00 80.72 C ATOM 251 ND1 HIS A 35 28.230 75.772 3.167 1.00 82.07 N ATOM 252 CD2 HIS A 35 28.535 75.842 0.987 1.00 80.45 C ATOM 253 CE1 HIS A 35 28.462 77.053 2.816 1.00 87.35 C ATOM 254 NE2 HIS A 35 28.641 77.094 1.480 1.00 82.51 N ATOM 255 N GLU A 36 26.189 70.865 2.963 1.00 47.05 N ATOM 256 CA GLU A 36 25.667 69.507 2.771 1.00 51.19 C ATOM 257 C GLU A 36 24.325 69.578 2.009 1.00 61.53 C ATOM 258 O GLU A 36 24.102 68.819 1.031 1.00 59.78 O ATOM 259 CB GLU A 36 25.472 68.791 4.117 1.00 47.97 C ATOM 260 CG GLU A 36 25.076 67.319 4.018 1.00 52.48 C ATOM 261 CD GLU A 36 24.919 66.640 5.387 1.00 63.88 C ATOM 262 OE1 GLU A 36 25.625 67.023 6.346 1.00 73.74 O ATOM 263 OE2 GLU A 36 24.076 65.724 5.532 1.00 64.59 O ATOM 264 N ILE A 37 23.451 70.504 2.445 1.00 58.25 N ATOM 265 CA ILE A 37 22.115 70.621 1.882 1.00 56.95 C ATOM 266 C ILE A 37 22.208 70.988 0.414 1.00 59.53 C ATOM 267 O ILE A 37 21.659 70.289 −0.448 1.00 62.54 O ATOM 268 CB ILE A 37 21.253 71.605 2.675 1.00 56.86 C ATOM 269 CG1 ILE A 37 20.604 70.896 3.858 1.00 59.71 C ATOM 270 CG2 ILE A 37 20.149 72.159 1.821 1.00 55.03 C ATOM 271 CD1 ILE A 37 20.294 71.799 5.030 1.00 53.48 C ATOM 272 N ILE A 38 22.942 72.049 0.130 1.00 55.45 N ATOM 273 CA ILE A 38 23.128 72.477 −1.248 1.00 62.73 C ATOM 274 C ILE A 38 23.741 71.404 −2.125 1.00 62.25 C ATOM 275 O ILE A 38 23.317 71.181 −3.269 1.00 62.70 O ATOM 276 CB ILE A 38 24.030 73.716 −1.310 1.00 68.78 C ATOM 277 CG1 ILE A 38 23.383 74.841 −0.488 1.00 64.29 C ATOM 278 CG2 ILE A 38 24.346 74.095 −2.761 1.00 57.22 C ATOM 279 CD1 ILE A 38 24.159 76.129 −0.518 1.00 68.97 C ATOM 280 N GLU A 39 24.751 70.740 −1.590 1.00 69.88 N ATOM 281 CA GLU A 39 25.476 69.751 −2.368 1.00 70.71 C ATOM 282 C GLU A 39 24.569 68.571 −2.680 1.00 67.85 C ATOM 283 O GLU A 39 24.570 68.069 −3.815 1.00 65.96 O ATOM 284 CB GLU A 39 26.702 69.291 −1.610 1.00 79.61 C ATOM 285 CG GLU A 39 27.971 69.389 −2.419 1.00 93.30 C ATOM 286 CD GLU A 39 28.468 70.807 −2.468 1.00 104.34 C ATOM 287 OE1 GLU A 39 29.082 71.242 −1.455 1.00 105.63 O ATOM 288 OE2 GLU A 39 28.237 71.467 −3.515 1.00 103.58 O ATOM 289 N THR A 40 23.774 68.156 −1.687 1.00 57.26 N ATOM 290 CA THR A 40 22.807 67.089 −1.907 1.00 55.23 C ATOM 291 C THR A 40 21.804 67.447 −3.008 1.00 57.35 C ATOM 292 O THR A 40 21.558 66.660 −3.921 1.00 58.36 O ATOM 293 CB THR A 40 22.038 66.748 −0.643 1.00 57.10 C ATOM 294 OG1 THR A 40 22.954 66.445 0.433 1.00 54.49 O ATOM 295 CG2 THR A 40 21.139 65.582 −0.930 1.00 50.19 C ATOM 296 N ILE A 41 21.245 68.649 −2.941 1.00 57.83 N ATOM 297 CA ILE A 41 20.336 69.080 −3.979 1.00 57.80 C ATOM 298 C ILE A 41 21.012 68.968 −5.344 1.00 65.51 C ATOM 299 O ILE A 41 20.441 68.396 −6.297 1.00 67.17 O ATOM 300 CB ILE A 41 19.791 70.490 −3.705 1.00 60.56 C ATOM 301 CG1 ILE A 41 18.770 70.440 −2.547 1.00 65.58 C ATOM 302 CG2 ILE A 41 19.163 71.072 −4.961 1.00 58.32 C ATOM 303 CD1 ILE A 41 18.344 71.800 −2.009 1.00 58.69 C ATOM 304 N ARG A 42 22.241 69.477 −5.439 1.00 71.84 N ATOM 305 CA ARG A 42 22.942 69.462 −6.715 1.00 67.37 C ATOM 306 C ARG A 42 23.156 68.042 −7.189 1.00 65.96 C ATOM 307 O ARG A 42 22.913 67.743 −8.371 1.00 65.55 O ATOM 308 CB ARG A 42 24.263 70.199 −6.622 1.00 82.71 C ATOM 309 CG ARG A 42 24.236 71.612 −7.183 1.00 91.22 C ATOM 310 CD ARG A 42 23.831 72.597 −6.112 1.00 101.12 C ATOM 311 NE ARG A 42 24.116 73.987 −6.468 1.00 121.12 N ATOM 312 CZ ARG A 42 25.313 74.560 −6.383 1.00 116.46 C ATOM 313 NH1 ARG A 42 25.439 75.839 −6.711 1.00 115.56 N ATOM 314 NH2 ARG A 42 26.376 73.864 −5.979 1.00 104.93 N ATOM 315 N TRP A 43 23.557 67.157 −6.267 1.00 59.20 N ATOM 316 CA TRP A 43 23.744 65.754 −6.631 1.00 63.08 C ATOM 317 C TRP A 43 22.511 65.089 −7.125 1.00 73.03 C ATOM 318 O TRP A 43 22.560 64.394 −8.154 1.00 73.53 O ATOM 319 CB TRP A 43 24.473 64.937 −5.555 1.00 65.57 C ATOM 320 CG TRP A 43 25.945 65.234 −5.690 1.00 66.23 C ATOM 321 CD1 TRP A 43 26.739 66.008 −4.857 1.00 63.43 C ATOM 322 CD2 TRP A 43 26.806 64.886 −6.822 1.00 58.94 C ATOM 323 NE1 TRP A 43 27.998 66.125 −5.369 1.00 61.08 N ATOM 324 CE2 TRP A 43 28.099 65.474 −6.544 1.00 57.84 C ATOM 325 CE3 TRP A 43 26.639 64.135 −7.984 1.00 62.14 C ATOM 326 CZ2 TRP A 43 29.170 65.318 −7.401 1.00 58.37 C ATOM 327 CZ3 TRP A 43 27.731 63.972 −8.837 1.00 57.49 C ATOM 328 CH2 TRP A 43 28.962 64.558 −8.552 1.00 55.92 C ATOM 329 N VAL A 44 21.380 65.326 −6.451 1.00 73.53 N ATOM 330 CA VAL A 44 20.126 64.746 −6.919 1.00 69.07 C ATOM 331 C VAL A 44 19.735 65.234 −8.323 1.00 66.53 C ATOM 332 O VAL A 44 19.263 64.435 −9.152 1.00 64.21 O ATOM 333 CB VAL A 44 18.994 64.886 −5.909 1.00 74.63 C ATOM 334 CG1 VAL A 44 17.733 64.249 −6.472 1.00 73.99 C ATOM 335 CG2 VAL A 44 19.386 64.204 −4.605 1.00 74.06 C ATOM 336 N CYS A 45 19.983 66.504 −8.633 1.00 57.28 N ATOM 337 CA CYS A 45 19.795 66.914 −10.028 1.00 63.19 C ATOM 338 C CYS A 45 20.654 66.132 −11.026 1.00 70.69 C ATOM 339 O CYS A 45 20.277 66.041 −12.185 1.00 82.95 O ATOM 340 CB CYS A 45 19.953 68.415 −10.219 1.00 64.68 C ATOM 341 SG CYS A 45 18.984 69.366 −9.019 1.00 75.91 S ATOM 342 N GLU A 46 21.791 65.569 −10.603 1.00 73.56 N ATOM 343 CA GLU A 46 22.610 64.769 −11.537 1.00 72.24 C ATOM 344 C GLU A 46 22.056 63.386 −11.703 1.00 73.66 C ATOM 345 O GLU A 46 22.240 62.774 −12.756 1.00 83.16 O ATOM 346 CB GLU A 46 24.086 64.637 −11.127 1.00 75.63 C ATOM 347 CG GLU A 46 24.852 65.933 −10.959 1.00 79.40 C ATOM 348 CD GLU A 46 24.901 66.766 −12.221 1.00 83.95 C ATOM 349 OE1 GLU A 46 25.162 66.203 −13.313 1.00 81.43 O ATOM 350 OE2 GLU A 46 24.690 67.994 −12.102 1.00 90.40 O ATOM 351 N GLU A 47 21.421 62.857 −10.661 1.00 70.52 N ATOM 352 CA GLU A 47 20.780 61.553 −10.803 1.00 74.85 C ATOM 353 C GLU A 47 19.608 61.688 −11.765 1.00 79.90 C ATOM 354 O GLU A 47 19.370 60.818 −12.592 1.00 88.55 O ATOM 355 CB GLU A 47 20.232 61.032 −9.480 1.00 77.96 C ATOM 356 CG GLU A 47 21.212 60.895 −8.331 1.00 76.05 C ATOM 357 CD GLU A 47 20.618 60.055 −7.208 1.00 77.04 C ATOM 358 OE1 GLU A 47 20.224 60.591 −6.148 1.00 80.59 O ATOM 359 OE2 GLU A 47 20.517 58.836 −7.391 1.00 81.05 O ATOM 360 N ILE A 48 18.872 62.787 −11.647 1.00 79.18 N ATOM 361 CA ILE A 48 17.650 62.931 −12.394 1.00 76.42 C ATOM 362 C ILE A 48 17.727 64.167 −13.274 1.00 84.13 C ATOM 363 O ILE A 48 17.429 65.291 −12.836 1.00 85.83 O ATOM 364 CB ILE A 48 16.416 62.947 −11.472 1.00 76.61 C ATOM 365 CG1 ILE A 48 16.433 61.725 −10.566 1.00 77.66 C ATOM 366 CG2 ILE A 48 15.150 62.857 −12.297 1.00 87.70 C ATOM 367 CD1 ILE A 48 15.557 61.839 −9.344 1.00 77.11 C ATOM 368 N PRO A 49 18.132 63.962 −14.534 1.00 82.54 N ATOM 369 CA PRO A 49 18.185 65.052 −15.503 1.00 79.22 C ATOM 370 C PRO A 49 16.894 65.867 −15.474 1.00 84.11 C ATOM 371 O PRO A 49 16.931 67.099 −15.571 1.00 81.77 O ATOM 372 CB PRO A 49 18.323 64.323 −16.840 1.00 78.41 C ATOM 373 CG PRO A 49 18.955 63.003 −16.504 1.00 78.63 C ATOM 374 CD PRO A 49 18.559 62.665 −15.097 1.00 78.84 C ATOM 375 N ASP A 50 15.764 65.174 −15.328 1.00 90.72 N ATOM 376 CA ASP A 50 14.444 65.815 −15.292 1.00 89.42 C ATOM 377 C ASP A 50 14.304 66.821 −14.155 1.00 87.00 C ATOM 378 O ASP A 50 13.857 67.955 −14.365 1.00 84.40 O ATOM 379 CB ASP A 50 13.338 64.763 −15.227 1.00 99.33 C ATOM 380 CG ASP A 50 12.892 64.285 −16.609 1.00 102.05 C ATOM 381 OD1 ASP A 50 13.165 64.987 −17.608 1.00 104.36 O ATOM 382 OD2 ASP A 50 12.257 63.208 −16.696 1.00 97.76 O ATOM 383 N LEU A 51 14.714 66.418 −12.955 1.00 86.81 N ATOM 384 CA LEU A 51 14.759 67.341 −11.816 1.00 82.70 C ATOM 385 C LEU A 51 15.630 68.551 −12.127 1.00 81.31 C ATOM 386 O LEU A 51 15.356 69.672 −11.700 1.00 76.65 O ATOM 387 CB LEU A 51 15.317 66.629 −10.602 1.00 76.35 C ATOM 388 CG LEU A 51 15.191 67.430 −9.323 1.00 80.32 C ATOM 389 CD1 LEU A 51 13.781 67.292 −8.787 1.00 83.45 C ATOM 390 CD2 LEU A 51 16.182 66.897 −8.305 1.00 82.46 C ATOM 391 N LYS A 52 16.696 68.300 −12.877 1.00 87.09 N ATOM 392 CA LYS A 52 17.619 69.342 −13.258 1.00 94.60 C ATOM 393 C LYS A 52 16.851 70.365 −14.064 1.00 95.07 C ATOM 394 O LYS A 52 16.966 71.573 −13.828 1.00 90.68 O ATOM 395 CB LYS A 52 18.730 68.734 −14.099 1.00 104.05 C ATOM 396 CG LYS A 52 19.996 69.553 −14.212 1.00 100.91 C ATOM 397 CD LYS A 52 20.981 68.759 −15.037 1.00 102.41 C ATOM 398 CE LYS A 52 22.366 68.838 −14.440 1.00 107.90 C ATOM 399 NZ LYS A 52 23.204 67.750 −15.007 1.00 110.42 N ATOM 400 N LEU A 53 16.048 69.865 −15.001 1.00 94.63 N ATOM 401 CA LEU A 53 15.274 70.729 −15.878 1.00 93.67 C ATOM 402 C LEU A 53 14.321 71.601 −15.070 1.00 93.74 C ATOM 403 O LEU A 53 14.181 72.780 −15.359 1.00 98.19 O ATOM 404 CB LEU A 53 14.539 69.917 −16.953 1.00 90.70 C ATOM 405 CG LEU A 53 15.407 69.304 −18.065 1.00 104.24 C ATOM 406 CD1 LEU A 53 14.688 68.183 −18.816 1.00 101.19 C ATOM 407 CD2 LEU A 53 15.928 70.365 −19.039 1.00 94.60 C ATOM 408 N ALA A 54 13.710 71.032 −14.031 1.00 91.95 N ATOM 409 CA ALA A 54 12.753 71.770 −13.197 1.00 92.17 C ATOM 410 C ALA A 54 13.373 72.903 −12.386 1.00 100.00 C ATOM 411 O ALA A 54 12.656 73.758 −11.866 1.00 111.75 O ATOM 412 CB ALA A 54 12.027 70.820 −12.258 1.00 83.09 C ATOM 413 N MET A 55 14.695 72.914 −12.261 1.00 103.41 N ATOM 414 CA MET A 55 15.318 73.797 −11.283 1.00 104.99 C ATOM 415 C MET A 55 16.428 74.704 −11.792 1.00 112.02 C ATOM 416 O MET A 55 17.322 75.071 −11.020 1.00 116.02 O ATOM 417 CB MET A 55 15.856 72.967 −10.135 1.00 99.26 C ATOM 418 CG MET A 55 14.793 72.228 −9.372 1.00 92.81 C ATOM 419 SD MET A 55 15.538 71.706 −7.839 1.00 98.58 S ATOM 420 CE MET A 55 15.406 73.181 −6.834 1.00 91.46 C ATOM 421 N GLU A 56 16.369 75.086 −13.067 1.00 113.40 N ATOM 422 CA GLU A 56 17.344 76.021 −13.633 1.00 117.21 C ATOM 423 C GLU A 56 17.299 77.372 −12.911 1.00 120.50 C ATOM 424 O GLU A 56 17.604 78.412 −13.491 1.00 130.81 O ATOM 425 CB GLU A 56 17.112 76.187 −15.136 1.00 127.96 C ATOM 426 CG GLU A 56 17.011 74.860 −15.879 1.00 141.64 C ATOM 427 CD GLU A 56 17.109 75.003 −17.389 1.00 142.62 C ATOM 428 OE1 GLU A 56 16.057 74.904 −18.054 1.00 140.03 O ATOM 429 OE2 GLU A 56 18.230 75.207 −17.910 1.00 138.88 O ATOM 430 N ASN A 57 16.903 77.324 −11.639 1.00 121.75 N ATOM 431 CA ASN A 57 16.816 78.479 −10.749 1.00 126.58 C ATOM 432 C ASN A 57 17.400 78.115 −9.370 1.00 129.88 C ATOM 433 O ASN A 57 16.980 77.123 −8.761 1.00 117.68 O ATOM 434 CB ASN A 57 15.354 78.935 −10.579 1.00 126.36 C ATOM 435 CG ASN A 57 14.386 78.230 −11.527 1.00 129.24 C ATOM 436 OD1 ASN A 57 13.618 77.350 −11.109 1.00 123.56 O ATOM 437 ND2 ASN A 57 14.416 78.613 −12.809 1.00 117.82 N ATOM 438 N TYR A 58 18.370 78.908 −8.899 1.00 136.08 N ATOM 439 CA TYR A 58 18.910 78.811 −7.522 1.00 139.28 C ATOM 440 C TYR A 58 19.772 80.021 −7.107 1.00 141.18 C ATOM 441 O TYR A 58 20.918 80.195 −7.535 1.00 133.88 O ATOM 442 CB TYR A 58 19.659 77.488 −7.287 1.00 139.24 C ATOM 443 CG TYR A 58 20.882 77.319 −8.149 1.00 149.12 C ATOM 444 CD1 TYR A 58 22.161 77.428 −7.603 1.00 143.38 C ATOM 445 CD2 TYR A 58 20.759 77.069 −9.517 1.00 146.78 C ATOM 446 CE1 TYR A 58 23.280 77.288 −8.398 1.00 141.67 C ATOM 447 CE2 TYR A 58 21.871 76.932 −10.319 1.00 141.89 C ATOM 448 CZ TYR A 58 23.126 77.037 −9.756 1.00 142.17 C ATOM 449 OH TYR A 58 24.224 76.890 −10.564 1.00 140.68 O ATOM 450 N ASP A 62 24.971 80.518 −6.604 1.00 126.07 N ATOM 451 CA ASP A 62 25.035 81.417 −5.455 1.00 128.01 C ATOM 452 C ASP A 62 23.700 81.495 −4.730 1.00 129.10 C ATOM 453 O ASP A 62 22.635 81.411 −5.360 1.00 125.04 O ATOM 454 CB ASP A 62 25.499 82.818 −5.867 1.00 132.09 C ATOM 455 CG ASP A 62 26.984 83.051 −5.605 1.00 136.60 C ATOM 456 OD1 ASP A 62 27.498 84.107 −6.036 1.00 134.17 O ATOM 457 OD2 ASP A 62 27.634 82.191 −4.968 1.00 131.49 O ATOM 458 N TYR A 63 23.779 81.670 −3.407 1.00 121.64 N ATOM 459 CA TYR A 63 22.632 81.520 −2.515 1.00 117.94 C ATOM 460 C TYR A 63 22.986 81.915 −1.088 1.00 114.45 C ATOM 461 O TYR A 63 24.145 81.794 −0.695 1.00 119.70 O ATOM 462 CB TYR A 63 22.176 80.065 −2.521 1.00 125.39 C ATOM 463 CG TYR A 63 20.690 79.944 −2.554 1.00 136.22 C ATOM 464 CD1 TYR A 63 20.017 79.715 −3.755 1.00 142.39 C ATOM 465 CD2 TYR A 63 19.944 80.091 −1.393 1.00 142.75 C ATOM 466 CE1 TYR A 63 18.635 79.618 −3.792 1.00 149.23 C ATOM 467 CE2 TYR A 63 18.566 80.000 −1.417 1.00 150.31 C ATOM 468 CZ TYR A 63 17.913 79.764 −2.611 1.00 154.31 C ATOM 469 OH TYR A 63 16.538 79.676 −2.607 1.00 161.61 O ATOM 470 N ASP A 64 21.999 82.356 −0.301 1.00 108.85 N ATOM 471 CA ASP A 64 22.283 82.807 1.075 1.00 107.46 C ATOM 472 C ASP A 64 21.971 81.808 2.176 1.00 105.51 C ATOM 473 O ASP A 64 20.816 81.537 2.522 1.00 101.01 O ATOM 474 CB ASP A 64 21.664 84.168 1.414 1.00 106.61 C ATOM 475 CG ASP A 64 21.755 84.485 2.912 1.00 112.70 C ATOM 476 OD1 ASP A 64 22.850 84.822 3.401 1.00 105.14 O ATOM 477 OD2 ASP A 64 20.733 84.367 3.613 1.00 121.07 O ATOM 478 N THR A 65 23.046 81.316 2.766 1.00 104.67 N ATOM 479 CA THR A 65 23.002 80.150 3.620 1.00 100.34 C ATOM 480 C THR A 65 22.802 80.519 5.087 1.00 98.44 C ATOM 481 O THR A 65 22.643 79.641 5.952 1.00 93.97 O ATOM 482 CB THR A 65 24.274 79.286 3.407 1.00 99.05 C ATOM 483 OG1 THR A 65 25.386 79.866 4.091 1.00 100.03 O ATOM 484 CG2 THR A 65 24.624 79.194 1.913 1.00 98.98 C ATOM 485 N LYS A 66 22.810 81.821 5.372 1.00 107.87 N ATOM 486 CA LYS A 66 22.603 82.269 6.748 1.00 114.46 C ATOM 487 C LYS A 66 21.185 82.775 7.005 1.00 106.58 C ATOM 488 O LYS A 66 20.767 82.864 8.158 1.00 104.42 O ATOM 489 CB LYS A 66 23.683 83.262 7.217 1.00 114.35 C ATOM 490 CG LYS A 66 23.903 83.276 8.741 1.00 130.48 C ATOM 491 CD LYS A 66 24.839 82.177 9.270 1.00 130.50 C ATOM 492 CE LYS A 66 24.139 80.848 9.581 1.00 126.24 C ATOM 493 NZ LYS A 66 23.583 80.749 10.961 1.00 111.84 N ATOM 494 N SER A 67 20.442 83.075 5.939 1.00 101.94 N ATOM 495 CA SER A 67 19.020 83.380 6.084 1.00 107.41 C ATOM 496 C SER A 67 18.193 82.125 5.946 1.00 96.08 C ATOM 497 O SER A 67 18.203 81.490 4.896 1.00 97.48 O ATOM 498 CB SER A 67 18.545 84.408 5.053 1.00 115.14 C ATOM 499 OG SER A 67 17.156 84.662 5.207 1.00 119.22 O ATOM 500 N PHE A 68 17.467 81.785 7.003 1.00 89.83 N ATOM 501 CA PHE A 68 16.573 80.630 6.991 1.00 90.42 C ATOM 502 C PHE A 68 15.548 80.694 5.860 1.00 97.62 C ATOM 503 O PHE A 68 15.300 79.704 5.171 1.00 101.27 O ATOM 504 CB PHE A 68 15.861 80.534 8.326 1.00 83.80 C ATOM 505 CG PHE A 68 14.836 79.446 8.391 1.00 88.70 C ATOM 506 CD1 PHE A 68 14.926 78.455 9.357 1.00 95.02 C ATOM 507 CD2 PHE A 68 13.760 79.424 7.513 1.00 83.47 C ATOM 508 CE1 PHE A 68 13.970 77.453 9.433 1.00 99.19 C ATOM 509 CE2 PHE A 68 12.807 78.429 7.580 1.00 85.15 C ATOM 510 CZ PHE A 68 12.903 77.445 8.546 1.00 96.44 C ATOM 511 N GLU A 69 14.944 81.864 5.693 1.00 105.48 N ATOM 512 CA GLU A 69 14.030 82.124 4.588 1.00 106.47 C ATOM 513 C GLU A 69 14.681 81.792 3.242 1.00 97.73 C ATOM 514 O GLU A 69 14.071 81.131 2.402 1.00 100.49 O ATOM 515 CB GLU A 69 13.568 83.589 4.638 1.00 120.62 C ATOM 516 CG GLU A 69 12.866 84.118 3.391 1.00 127.65 C ATOM 517 CD GLU A 69 12.661 85.626 3.439 1.00 150.89 C ATOM 518 OE1 GLU A 69 11.520 86.079 3.202 1.00 163.68 O ATOM 519 OE2 GLU A 69 13.635 86.363 3.724 1.00 152.96 O ATOM 520 N SER A 70 15.918 82.246 3.049 1.00 91.25 N ATOM 521 CA SER A 70 16.651 81.978 1.815 1.00 84.80 C ATOM 522 C SER A 70 16.944 80.480 1.648 1.00 91.08 C ATOM 523 O SER A 70 16.812 79.944 0.548 1.00 91.69 O ATOM 524 CB SER A 70 17.938 82.787 1.776 1.00 80.66 C ATOM 525 OG SER A 70 18.656 82.517 0.588 1.00 79.86 O ATOM 526 N MET A 71 17.317 79.810 2.740 1.00 88.99 N ATOM 527 CA MET A 71 17.487 78.356 2.738 1.00 87.92 C ATOM 528 C MET A 71 16.188 77.615 2.431 1.00 85.78 C ATOM 529 O MET A 71 16.185 76.705 1.593 1.00 88.60 O ATOM 530 CB MET A 71 18.096 77.833 4.061 1.00 93.69 C ATOM 531 CG MET A 71 19.615 77.973 4.186 1.00 88.13 C ATOM 532 SD MET A 71 20.553 77.476 2.716 1.00 88.52 S ATOM 533 CE MET A 71 20.390 75.702 2.868 1.00 88.78 C ATOM 534 N GLN A 72 15.092 78.004 3.088 1.00 82.82 N ATOM 535 CA GLN A 72 13.821 77.284 2.910 1.00 81.80 C ATOM 536 C GLN A 72 13.175 77.379 1.536 1.00 73.25 C ATOM 537 O GLN A 72 12.512 76.447 1.115 1.00 74.61 O ATOM 538 CB GLN A 72 12.801 77.625 3.973 1.00 80.12 C ATOM 539 CG GLN A 72 11.702 76.582 4.029 1.00 85.60 C ATOM 540 CD GLN A 72 10.848 76.722 5.269 1.00 96.93 C ATOM 541 OE1 GLN A 72 10.414 77.824 5.614 1.00 95.17 O ATOM 542 NE2 GLN A 72 10.604 75.604 5.953 1.00 93.88 N ATOM 543 N ARG A 73 13.371 78.486 0.835 1.00 77.67 N ATOM 544 CA ARG A 73 12.896 78.570 −0.538 1.00 91.82 C ATOM 545 C ARG A 73 13.546 77.456 −1.322 1.00 89.42 C ATOM 546 O ARG A 73 12.883 76.787 −2.126 1.00 91.85 O ATOM 547 CB ARG A 73 13.230 79.916 −1.181 1.00 101.22 C ATOM 548 CG ARG A 73 12.274 81.014 −0.785 1.00 113.69 C ATOM 549 CD ARG A 73 12.564 82.306 −1.525 1.00 121.96 C ATOM 550 NE ARG A 73 11.885 83.415 −0.861 1.00 137.41 N ATOM 551 CZ ARG A 73 10.578 83.669 −0.951 1.00 145.86 C ATOM 552 NH1 ARG A 73 9.783 82.901 −1.692 1.00 142.04 N ATOM 553 NH2 ARG A 73 10.062 84.702 −0.296 1.00 147.81 N ATOM 554 N LEU A 74 14.843 77.259 −1.062 1.00 86.56 N ATOM 555 CA LEU A 74 15.642 76.250 −1.756 1.00 77.33 C ATOM 556 C LEU A 74 15.135 74.846 −1.454 1.00 76.87 C ATOM 557 O LEU A 74 14.871 74.068 −2.386 1.00 68.75 O ATOM 558 CB LEU A 74 17.129 76.387 −1.422 1.00 79.09 C ATOM 559 CG LEU A 74 18.119 75.337 −1.955 1.00 77.59 C ATOM 560 CD1 LEU A 74 18.173 75.258 −3.476 1.00 73.46 C ATOM 561 CD2 LEU A 74 19.496 75.607 −1.389 1.00 75.07 C ATOM 562 N CYS A 75 14.979 74.522 −0.171 1.00 67.63 N ATOM 563 CA CYS A 75 14.421 73.231 0.175 1.00 73.22 C ATOM 564 C CYS A 75 13.039 73.036 −0.444 1.00 79.42 C ATOM 565 O CYS A 75 12.753 71.960 −0.992 1.00 81.19 O ATOM 566 CB CYS A 75 14.398 73.040 1.679 1.00 81.22 C ATOM 567 SG CYS A 75 16.069 73.066 2.354 1.00 84.64 S ATOM 568 N ASP A 76 12.206 74.083 −0.393 1.00 81.32 N ATOM 569 CA ASP A 76 10.854 74.018 −0.939 1.00 80.83 C ATOM 570 C ASP A 76 10.874 73.775 −2.431 1.00 77.44 C ATOM 571 O ASP A 76 10.290 72.807 −2.903 1.00 74.40 O ATOM 572 CB ASP A 76 10.040 75.259 −0.595 1.00 91.09 C ATOM 573 CG ASP A 76 9.526 75.231 0.834 1.00 109.26 C ATOM 574 OD1 ASP A 76 8.977 76.263 1.283 1.00 117.74 O ATOM 575 OD2 ASP A 76 9.677 74.182 1.511 1.00 105.38 O ATOM 576 N LYS A 77 11.570 74.622 −3.178 1.00 73.07 N ATOM 577 CA LYS A 77 11.653 74.410 −4.617 1.00 80.26 C ATOM 578 C LYS A 77 12.043 72.954 −4.896 1.00 83.81 C ATOM 579 O LYS A 77 11.456 72.302 −5.770 1.00 93.85 O ATOM 580 CB LYS A 77 12.638 75.387 −5.285 1.00 85.13 C ATOM 581 CG LYS A 77 12.151 76.823 −5.497 1.00 95.80 C ATOM 582 CD LYS A 77 11.189 77.006 −6.683 1.00 112.15 C ATOM 583 CE LYS A 77 11.644 76.325 −7.980 1.00 122.30 C ATOM 584 NZ LYS A 77 12.991 76.732 −8.493 1.00 125.25 N ATOM 585 N TYR A 78 13.009 72.444 −4.130 1.00 78.20 N ATOM 586 CA TYR A 78 13.538 71.108 −4.357 1.00 73.91 C ATOM 587 C TYR A 78 12.469 70.059 −4.066 1.00 72.35 C ATOM 588 O TYR A 78 12.107 69.284 −4.957 1.00 72.08 O ATOM 589 CB TYR A 78 14.855 70.856 −3.574 1.00 71.42 C ATOM 590 CG TYR A 78 15.203 69.386 −3.422 1.00 64.51 C ATOM 591 CD1 TYR A 78 15.735 68.650 −4.488 1.00 61.06 C ATOM 592 CD2 TYR A 78 14.944 68.722 −2.227 1.00 62.74 C ATOM 593 CE1 TYR A 78 16.022 67.295 −4.351 1.00 61.22 C ATOM 594 CE2 TYR A 78 15.216 67.370 −2.078 1.00 65.51 C ATOM 595 CZ TYR A 78 15.756 66.659 −3.136 1.00 64.77 C ATOM 596 OH TYR A 78 16.015 65.314 −2.961 1.00 69.46 O ATOM 597 N ASN A 79 11.955 70.038 −2.838 1.00 68.62 N ATOM 598 CA ASN A 79 10.869 69.106 −2.500 1.00 72.65 C ATOM 599 C ASN A 79 9.685 69.110 −3.494 1.00 72.06 C ATOM 600 O ASN A 79 9.203 68.061 −3.916 1.00 70.17 O ATOM 601 CB ASN A 79 10.385 69.372 −1.097 1.00 67.49 C ATOM 602 CG ASN A 79 11.470 69.156 −0.068 1.00 69.57 C ATOM 603 OD1 ASN A 79 11.925 68.037 0.129 1.00 78.52 O ATOM 604 ND2 ASN A 79 11.890 70.228 0.597 1.00 66.73 N ATOM 605 N ARG A 80 9.259 70.300 −3.889 1.00 71.81 N ATOM 606 CA ARG A 80 8.184 70.470 −4.844 1.00 68.65 C ATOM 607 C ARG A 80 8.555 69.854 −6.178 1.00 72.24 C ATOM 608 O ARG A 80 7.762 69.099 −6.771 1.00 78.48 O ATOM 609 CB ARG A 80 7.809 71.958 −4.980 1.00 70.70 C ATOM 610 CG ARG A 80 7.205 72.530 −3.695 1.00 74.40 C ATOM 611 CD ARG A 80 6.360 73.762 −3.938 1.00 83.67 C ATOM 612 NE ARG A 80 7.166 74.965 −4.111 1.00 94.25 N ATOM 613 CZ ARG A 80 7.355 75.885 −3.165 1.00 100.87 C ATOM 614 NH1 ARG A 80 8.124 76.938 −3.422 1.00 97.57 N ATOM 615 NH2 ARG A 80 6.791 75.749 −1.963 1.00 97.00 N ATOM 616 N ALA A 81 9.765 70.138 −6.653 1.00 74.35 N ATOM 617 CA ALA A 81 10.206 69.521 −7.906 1.00 71.16 C ATOM 618 C ALA A 81 10.272 67.998 −7.740 1.00 69.50 C ATOM 619 O ALA A 81 9.994 67.242 −8.673 1.00 71.80 O ATOM 620 CB ALA A 81 11.525 70.092 −8.364 1.00 64.33 C ATOM 621 N ILE A 82 10.589 67.552 −6.532 1.00 70.22 N ATOM 622 CA ILE A 82 10.635 66.125 −6.269 1.00 71.79 C ATOM 623 C ILE A 82 9.265 65.539 −6.514 1.00 70.91 C ATOM 624 O ILE A 82 9.125 64.621 −7.334 1.00 73.03 O ATOM 625 CB ILE A 82 11.174 65.786 −4.856 1.00 68.20 C ATOM 626 CG1 ILE A 82 12.690 65.876 −4.852 1.00 62.07 C ATOM 627 CG2 ILE A 82 10.812 64.364 −4.453 1.00 65.62 C ATOM 628 CD1 ILE A 82 13.356 64.918 −5.832 1.00 58.52 C ATOM 629 N ASP A 83 8.268 66.103 −5.825 1.00 71.85 N ATOM 630 CA ASP A 83 6.856 65.737 −6.001 1.00 66.02 C ATOM 631 C ASP A 83 6.544 65.715 −7.490 1.00 64.23 C ATOM 632 O ASP A 83 6.109 64.700 −8.043 1.00 63.57 O ATOM 633 CB ASP A 83 5.954 66.720 −5.250 1.00 58.99 C ATOM 634 CG ASP A 83 6.044 66.550 −3.736 1.00 68.14 C ATOM 635 OD1 ASP A 83 6.458 65.470 −3.244 1.00 73.63 O ATOM 636 OD2 ASP A 83 5.720 67.508 −3.020 1.00 75.85 O ATOM 637 N SER A 84 6.850 66.816 −8.157 1.00 58.55 N ATOM 638 CA SER A 84 6.669 66.858 −9.582 1.00 64.08 C ATOM 639 C SER A 84 7.259 65.628 −10.288 1.00 70.74 C ATOM 640 O SER A 84 6.646 65.062 −11.185 1.00 81.23 O ATOM 641 CB SER A 84 7.289 68.126 −10.119 1.00 66.16 C ATOM 642 OG SER A 84 7.439 68.000 −11.507 1.00 79.82 O ATOM 643 N ILE A 85 8.454 65.218 −9.883 1.00 76.70 N ATOM 644 CA ILE A 85 9.145 64.136 −10.565 1.00 74.98 C ATOM 645 C ILE A 85 8.425 62.825 −10.313 1.00 73.24 C ATOM 646 O ILE A 85 8.180 62.056 −11.250 1.00 71.23 O ATOM 647 CB ILE A 85 10.648 64.084 −10.162 1.00 76.94 C ATOM 648 CG1 ILE A 85 11.460 65.063 −11.019 1.00 74.86 C ATOM 649 CG2 ILE A 85 11.238 62.682 −10.273 1.00 65.77 C ATOM 650 CD1 ILE A 85 11.078 65.049 −12.485 1.00 78.80 C ATOM 651 N HIS A 86 8.080 62.583 −9.050 1.00 66.21 N ATOM 652 CA HIS A 86 7.372 61.370 −8.691 1.00 76.04 C ATOM 653 C HIS A 86 6.097 61.253 −9.474 1.00 85.86 C ATOM 654 O HIS A 86 5.690 60.155 −9.869 1.00 81.85 O ATOM 655 CB HIS A 86 7.087 61.358 −7.212 1.00 77.32 C ATOM 656 CG HIS A 86 8.307 61.108 −6.379 1.00 83.60 C ATOM 657 ND1 HIS A 86 8.518 61.719 −5.202 1.00 91.14 N ATOM 658 CD2 HIS A 86 9.414 60.288 −6.605 1.00 77.82 C ATOM 659 CE1 HIS A 86 9.691 61.294 −4.688 1.00 87.09 C ATOM 660 NE2 HIS A 86 10.238 60.428 −5.556 1.00 76.45 N ATOM 661 N GLN A 87 5.472 62.400 −9.729 1.00 83.88 N ATOM 662 CA GLN A 87 4.310 62.438 −10.576 1.00 81.50 C ATOM 663 C GLN A 87 4.655 61.913 −11.959 1.00 82.93 C ATOM 664 O GLN A 87 4.139 60.882 −12.360 1.00 94.72 O ATOM 665 CB GLN A 87 3.647 63.822 −10.587 1.00 79.79 C ATOM 666 CG GLN A 87 2.651 64.035 −9.436 1.00 78.40 C ATOM 667 CD GLN A 87 1.540 62.976 −9.367 1.00 81.75 C ATOM 668 OE1 GLN A 87 0.930 62.616 −10.380 1.00 93.67 O ATOM 669 NE2 GLN A 87 1.275 62.478 −8.170 1.00 76.50 N ATOM 670 N LEU A 88 5.565 62.577 −12.656 1.00 89.54 N ATOM 671 CA LEU A 88 6.074 62.083 −13.945 1.00 89.27 C ATOM 672 C LEU A 88 6.244 60.551 −14.046 1.00 90.72 C ATOM 673 O LEU A 88 5.975 59.954 −15.092 1.00 92.50 O ATOM 674 CB LEU A 88 7.393 62.776 −14.267 1.00 84.31 C ATOM 675 CG LEU A 88 7.868 62.785 −15.713 1.00 87.02 C ATOM 676 CD1 LEU A 88 6.736 63.161 −16.652 1.00 99.55 C ATOM 677 CD2 LEU A 88 9.008 63.774 −15.862 1.00 92.23 C ATOM 678 N TRP A 89 6.662 59.914 −12.958 1.00 86.97 N ATOM 679 CA TRP A 89 6.906 58.475 −12.988 1.00 95.62 C ATOM 680 C TRP A 89 5.672 57.628 −12.900 1.00 101.61 C ATOM 681 O TRP A 89 5.744 56.399 −13.015 1.00 114.72 O ATOM 682 CB TRP A 89 7.856 58.062 −11.877 1.00 98.45 C ATOM 683 CG TRP A 89 9.232 58.672 −11.949 1.00 96.77 C ATOM 684 CD1 TRP A 89 9.818 59.373 −13.009 1.00 93.23 C ATOM 685 CD2 TRP A 89 10.268 58.608 −10.913 1.00 100.86 C ATOM 686 NE1 TRP A 89 11.097 59.752 −12.695 1.00 87.91 N ATOM 687 CE2 TRP A 89 11.432 59.324 −11.453 1.00 93.56 C ATOM 688 CE3 TRP A 89 10.341 58.058 −9.623 1.00 100.33 C ATOM 689 CZ2 TRP A 89 12.602 59.470 −10.719 1.00 89.47 C ATOM 690 CZ3 TRP A 89 11.523 58.219 −8.892 1.00 88.13 C ATOM 691 CH2 TRP A 89 12.625 58.907 −9.428 1.00 90.79 C ATOM 692 N LYS A 90 4.531 58.257 −12.653 1.00 102.93 N ATOM 693 CA LYS A 90 3.257 57.545 −12.680 1.00 92.58 C ATOM 694 C LYS A 90 2.765 57.516 −14.123 1.00 97.63 C ATOM 695 O LYS A 90 2.170 56.524 −14.553 1.00 101.37 O ATOM 696 CB LYS A 90 2.247 58.212 −11.757 1.00 82.86 C ATOM 697 CG LYS A 90 2.564 58.055 −10.277 1.00 77.63 C ATOM 698 CD LYS A 90 1.956 59.193 −9.463 1.00 80.30 C ATOM 699 CE LYS A 90 2.123 58.963 −7.968 1.00 75.80 C ATOM 700 NZ LYS A 90 1.466 57.693 −7.578 1.00 82.12 N ATOM 701 N GLY A 91 3.045 58.600 −14.860 1.00 88.91 N ATOM 702 CA GLY A 91 2.852 58.664 −16.308 1.00 89.54 C ATOM 703 C GLY A 91 3.721 57.632 −16.992 1.00 100.34 C ATOM 704 O GLY A 91 4.349 56.808 −16.320 1.00 106.30 O ATOM 705 N THR A 92 3.774 57.657 −18.322 1.00 113.56 N ATOM 706 CA THR A 92 4.501 56.596 −19.047 1.00 124.37 C ATOM 707 C THR A 92 6.024 56.667 −18.911 1.00 127.99 C ATOM 708 O THR A 92 6.713 55.689 −19.209 1.00 139.09 O ATOM 709 CB THR A 92 4.083 56.440 −20.531 1.00 123.30 C ATOM 710 OG1 THR A 92 3.526 57.670 −21.018 1.00 124.09 O ATOM 711 CG2 THR A 92 3.057 55.308 −20.677 1.00 111.43 C ATOM 712 N THR A 93 6.537 57.808 −18.446 1.00 124.74 N ATOM 713 CA THR A 93 7.959 57.937 −18.133 1.00 128.33 C ATOM 714 C THR A 93 8.296 56.920 −17.054 1.00 131.44 C ATOM 715 O THR A 93 7.515 56.726 −16.116 1.00 132.48 O ATOM 716 CB THR A 93 8.320 59.349 −17.628 1.00 130.21 C ATOM 717 OG1 THR A 93 7.540 60.328 −18.330 1.00 131.88 O ATOM 718 CG2 THR A 93 9.822 59.638 −17.817 1.00 118.25 C ATOM 719 N GLN A 94 9.442 56.261 −17.207 1.00 131.90 N ATOM 720 CA GLN A 94 9.902 55.252 −16.250 1.00 130.17 C ATOM 721 C GLN A 94 10.865 55.832 −15.208 1.00 127.33 C ATOM 722 O GLN A 94 11.574 56.815 −15.485 1.00 107.01 O ATOM 723 CB GLN A 94 10.541 54.049 −16.961 1.00 131.32 C ATOM 724 CG GLN A 94 11.704 54.392 −17.877 1.00 143.44 C ATOM 725 CD GLN A 94 11.241 54.931 −19.218 1.00 153.35 C ATOM 726 OE1 GLN A 94 10.764 54.178 −20.069 1.00 161.04 O ATOM 727 NE2 GLN A 94 11.375 56.241 −19.411 1.00 152.41 N ATOM 728 N PRO A 95 10.879 55.231 −13.997 1.00 130.11 N ATOM 729 CA PRO A 95 11.812 55.644 −12.956 1.00 133.38 C ATOM 730 C PRO A 95 13.255 55.673 −13.443 1.00 143.04 C ATOM 731 O PRO A 95 13.642 54.890 −14.318 1.00 152.16 O ATOM 732 CB PRO A 95 11.657 54.554 −11.891 1.00 126.80 C ATOM 733 CG PRO A 95 10.261 54.074 −12.047 1.00 123.46 C ATOM 734 CD PRO A 95 9.936 54.202 −13.510 1.00 128.38 C ATOM 735 N MET A 96 14.020 56.610 −12.888 1.00 146.82 N ATOM 736 CA MET A 96 15.473 56.593 −12.918 1.00 138.87 C ATOM 737 C MET A 96 15.925 55.157 −12.638 1.00 146.28 C ATOM 738 O MET A 96 15.455 54.521 −11.675 1.00 131.23 O ATOM 739 CB MET A 96 15.998 57.565 −11.847 1.00 130.22 C ATOM 740 CG MET A 96 17.433 57.363 −11.367 1.00 130.45 C ATOM 741 SD MET A 96 17.625 57.551 −9.571 1.00 107.47 S ATOM 742 CE MET A 96 17.762 55.848 −9.035 1.00 109.11 C ATOM 743 N LYS A 97 16.804 54.645 −13.504 1.00 145.31 N ATOM 744 CA LYS A 97 17.333 53.291 −13.378 1.00 136.45 C ATOM 745 C LYS A 97 17.568 52.970 −11.904 1.00 133.95 C ATOM 746 O LYS A 97 18.369 53.629 −11.236 1.00 131.48 O ATOM 747 CB LYS A 97 18.607 53.141 −14.208 1.00 140.73 C ATOM 748 CG LYS A 97 18.341 52.858 −15.685 1.00 144.90 C ATOM 749 CD LYS A 97 19.612 52.823 −16.536 1.00 146.26 C ATOM 750 CE LYS A 97 20.734 51.987 −15.924 1.00 141.73 C ATOM 751 NZ LYS A 97 20.263 50.692 −15.351 1.00 135.31 N ATOM 752 N LEU A 98 16.838 51.969 −11.413 1.00 126.94 N ATOM 753 CA LEU A 98 16.679 51.708 −9.978 1.00 129.38 C ATOM 754 C LEU A 98 18.004 51.671 −9.202 1.00 128.73 C ATOM 755 O LEU A 98 18.471 52.703 −8.708 1.00 129.72 O ATOM 756 CB LEU A 98 15.873 50.413 −9.761 1.00 132.47 C ATOM 757 CG LEU A 98 14.673 50.377 −8.796 1.00 135.04 C ATOM 758 CD1 LEU A 98 14.042 48.986 −8.793 1.00 130.64 C ATOM 759 CD2 LEU A 98 15.015 50.821 −7.374 1.00 122.78 C ATOM 760 N ASN A 99 18.610 50.491 −9.104 1.00 124.55 N ATOM 761 CA ASN A 99 19.844 50.337 −8.337 1.00 117.94 C ATOM 762 C ASN A 99 21.152 50.249 −9.149 1.00 111.55 C ATOM 763 O ASN A 99 21.624 49.176 −9.532 1.00 107.36 O ATOM 764 CB ASN A 99 19.705 49.214 −7.304 1.00 120.86 C ATOM 765 CG ASN A 99 19.319 49.739 −5.930 1.00 130.51 C ATOM 766 OD1 ASN A 99 18.676 50.787 −5.807 1.00 128.58 O ATOM 767 ND2 ASN A 99 19.722 49.018 −4.884 1.00 126.01 N ATOM 768 N THR A 100 21.716 51.422 −9.401 1.00 99.27 N ATOM 769 CA THR A 100 23.004 51.559 −10.036 1.00 84.48 C ATOM 770 C THR A 100 24.037 51.916 −8.955 1.00 81.45 C ATOM 771 O THR A 100 23.679 52.129 −7.796 1.00 79.69 O ATOM 772 CB THR A 100 22.954 52.678 −11.082 1.00 90.64 C ATOM 773 OG1 THR A 100 22.728 53.928 −10.421 1.00 101.48 O ATOM 774 CG2 THR A 100 21.839 52.436 −12.089 1.00 84.67 C ATOM 775 N ARG A 101 25.318 51.950 −9.322 1.00 82.50 N ATOM 776 CA ARG A 101 26.379 52.358 −8.395 1.00 78.88 C ATOM 777 C ARG A 101 26.455 53.869 −8.460 1.00 67.03 C ATOM 778 O ARG A 101 26.168 54.454 −9.501 1.00 67.48 O ATOM 779 CB ARG A 101 27.754 51.801 −8.792 1.00 83.50 C ATOM 780 CG ARG A 101 27.851 50.305 −8.959 1.00 87.94 C ATOM 781 CD ARG A 101 27.958 49.620 −7.622 1.00 94.96 C ATOM 782 NE ARG A 101 27.838 48.176 −7.769 1.00 108.04 N ATOM 783 CZ ARG A 101 28.076 47.312 −6.794 1.00 113.43 C ATOM 784 NH1 ARG A 101 27.938 46.013 −7.017 1.00 125.92 N ATOM 785 NH2 ARG A 101 28.466 47.749 −5.603 1.00 113.65 N ATOM 786 N PRO A 102 26.845 54.508 −7.356 1.00 56.93 N ATOM 787 CA PRO A 102 26.973 55.947 −7.436 1.00 55.76 C ATOM 788 C PRO A 102 28.191 56.280 −8.251 1.00 60.15 C ATOM 789 O PRO A 102 29.167 55.557 −8.196 1.00 65.44 O ATOM 790 CB PRO A 102 27.192 56.378 −5.989 1.00 56.65 C ATOM 791 CG PRO A 102 27.561 55.139 −5.244 1.00 61.03 C ATOM 792 CD PRO A 102 26.950 53.992 −5.982 1.00 57.05 C ATOM 793 N SER A 103 28.133 57.367 −9.008 1.00 61.82 N ATOM 794 CA SER A 103 29.306 57.896 −9.663 1.00 55.75 C ATOM 795 C SER A 103 30.319 58.282 −8.586 1.00 60.21 C ATOM 796 O SER A 103 30.010 58.267 −7.385 1.00 61.78 O ATOM 797 CB SER A 103 28.900 59.129 −10.456 1.00 57.20 C ATOM 798 OG SER A 103 28.527 60.166 −9.565 1.00 62.31 O ATOM 799 N THR A 104 31.524 58.653 −9.000 1.00 63.33 N ATOM 800 CA THR A 104 32.560 58.948 −8.028 1.00 60.38 C ATOM 801 C THR A 104 32.188 60.184 −7.299 1.00 61.55 C ATOM 802 O THR A 104 32.177 60.201 −6.060 1.00 66.82 O ATOM 803 CB THR A 104 33.937 59.102 −8.680 1.00 62.90 C ATOM 804 OG1 THR A 104 34.346 57.809 −9.136 1.00 63.80 O ATOM 805 CG2 THR A 104 34.973 59.638 −7.676 1.00 56.51 C ATOM 806 N GLY A 105 31.858 61.216 −8.067 1.00 64.25 N ATOM 807 CA GLY A 105 31.432 62.494 −7.477 1.00 67.54 C ATOM 808 C GLY A 105 30.351 62.335 −6.419 1.00 69.90 C ATOM 809 O GLY A 105 30.435 62.913 −5.328 1.00 73.44 O ATOM 810 N LEU A 106 29.332 61.540 −6.725 1.00 63.26 N ATOM 811 CA LEU A 106 28.288 61.378 −5.763 1.00 63.45 C ATOM 812 C LEU A 106 28.840 60.679 −4.538 1.00 64.15 C ATOM 813 O LEU A 106 28.576 61.089 −3.404 1.00 66.48 O ATOM 814 CB LEU A 106 27.105 60.615 −6.358 1.00 65.67 C ATOM 815 CG LEU A 106 26.004 60.209 −5.367 1.00 62.67 C ATOM 816 CD1 LEU A 106 25.490 61.389 −4.571 1.00 68.09 C ATOM 817 CD2 LEU A 106 24.871 59.564 −6.130 1.00 65.84 C ATOM 818 N LEU A 107 29.601 59.617 −4.780 1.00 63.18 N ATOM 819 CA LEU A 107 30.163 58.810 −3.709 1.00 59.25 C ATOM 820 C LEU A 107 31.000 59.642 −2.740 1.00 56.53 C ATOM 821 O LEU A 107 30.907 59.461 −1.516 1.00 53.84 O ATOM 822 CB LEU A 107 31.021 57.701 −4.295 1.00 62.81 C ATOM 823 CG LEU A 107 31.523 56.654 −3.307 1.00 60.96 C ATOM 824 CD1 LEU A 107 30.447 56.370 −2.264 1.00 58.12 C ATOM 825 CD2 LEU A 107 31.908 55.401 −4.079 1.00 50.17 C ATOM 826 N ARG A 108 31.807 60.552 −3.279 1.00 48.39 N ATOM 827 CA ARG A 108 32.637 61.376 −2.422 1.00 51.93 C ATOM 828 C ARG A 108 31.704 62.171 −1.529 1.00 54.56 C ATOM 829 O ARG A 108 31.895 62.240 −0.313 1.00 57.93 O ATOM 830 CB ARG A 108 33.555 62.290 −3.238 1.00 55.00 C ATOM 831 CG ARG A 108 34.570 63.044 −2.398 1.00 64.84 C ATOM 832 CD ARG A 108 35.135 64.295 −3.069 1.00 71.28 C ATOM 833 NE ARG A 108 36.017 63.983 −4.190 1.00 85.87 N ATOM 834 CZ ARG A 108 35.622 63.854 −5.459 1.00 98.66 C ATOM 835 NH1 ARG A 108 34.346 64.015 −5.797 1.00 112.24 N ATOM 836 NH2 ARG A 108 36.506 63.559 −6.405 1.00 103.90 N ATOM 837 N HIS A 109 30.652 62.730 −2.128 1.00 61.45 N ATOM 838 CA HIS A 109 29.640 63.464 −1.357 1.00 56.46 C ATOM 839 C HIS A 109 29.029 62.608 −0.303 1.00 57.01 C ATOM 840 O HIS A 109 29.123 62.934 0.890 1.00 56.24 O ATOM 841 CB HIS A 109 28.556 64.044 −2.243 1.00 61.80 C ATOM 842 CG HIS A 109 27.449 64.691 −1.466 1.00 67.05 C ATOM 843 ND1 HIS A 109 27.594 65.885 −0.865 1.00 67.02 N ATOM 844 CD2 HIS A 109 26.166 64.243 −1.161 1.00 62.56 C ATOM 845 CE1 HIS A 109 26.464 66.185 −0.212 1.00 63.34 C ATOM 846 NE2 HIS A 109 25.593 65.174 −0.394 1.00 63.52 N ATOM 847 N ILE A 110 28.427 61.487 −0.712 1.00 53.30 N ATOM 848 CA ILE A 110 27.773 60.609 0.253 1.00 53.14 C ATOM 849 C ILE A 110 28.687 60.290 1.424 1.00 57.87 C ATOM 850 O ILE A 110 28.265 60.311 2.577 1.00 57.73 O ATOM 851 CB ILE A 110 27.400 59.275 −0.362 1.00 53.96 C ATOM 852 CG1 ILE A 110 26.405 59.466 −1.507 1.00 59.80 C ATOM 853 CG2 ILE A 110 26.884 58.361 0.732 1.00 50.95 C ATOM 854 CD1 ILE A 110 25.724 58.186 −1.920 1.00 58.03 C ATOM 855 N LEU A 111 29.946 59.973 1.127 1.00 60.59 N ATOM 856 CA LEU A 111 30.845 59.535 2.181 1.00 62.61 C ATOM 857 C LEU A 111 31.183 60.688 3.115 1.00 63.24 C ATOM 858 O LEU A 111 31.341 60.497 4.324 1.00 63.63 O ATOM 859 CB LEU A 111 32.099 58.885 1.606 1.00 65.04 C ATOM 860 CG LEU A 111 31.953 57.466 1.037 1.00 65.15 C ATOM 861 CD1 LEU A 111 33.184 57.087 0.225 1.00 58.67 C ATOM 862 CD2 LEU A 111 31.713 56.452 2.142 1.00 63.50 C ATOM 863 N GLN A 112 31.266 61.892 2.556 1.00 60.51 N ATOM 864 CA GLN A 112 31.465 63.074 3.369 1.00 58.56 C ATOM 865 C GLN A 112 30.292 63.183 4.351 1.00 62.16 C ATOM 866 O GLN A 112 30.473 63.430 5.542 1.00 63.02 O ATOM 867 CB GLN A 112 31.562 64.279 2.460 1.00 57.15 C ATOM 868 CG GLN A 112 31.897 65.580 3.153 1.00 68.74 C ATOM 869 CD GLN A 112 33.194 65.517 3.930 1.00 76.93 C ATOM 870 OE1 GLN A 112 33.209 65.696 5.150 1.00 83.36 O ATOM 871 NE2 GLN A 112 34.295 65.269 3.227 1.00 80.34 N ATOM 872 N GLN A 113 29.093 62.920 3.840 1.00 61.95 N ATOM 873 CA GLN A 113 27.845 63.093 4.569 1.00 58.69 C ATOM 874 C GLN A 113 27.820 62.091 5.703 1.00 63.45 C ATOM 875 O GLN A 113 27.680 62.457 6.872 1.00 67.22 O ATOM 876 CB GLN A 113 26.729 62.822 3.585 1.00 60.48 C ATOM 877 CG GLN A 113 25.409 63.484 3.826 1.00 63.50 C ATOM 878 CD GLN A 113 24.564 63.488 2.567 1.00 68.85 C ATOM 879 OE1 GLN A 113 24.746 62.664 1.674 1.00 64.48 O ATOM 880 NE2 GLN A 113 23.647 64.436 2.480 1.00 75.50 N ATOM 881 N VAL A 114 28.007 60.822 5.343 1.00 66.90 N ATOM 882 CA VAL A 114 28.072 59.715 6.298 1.00 65.23 C ATOM 883 C VAL A 114 29.078 59.996 7.430 1.00 64.65 C ATOM 884 O VAL A 114 28.779 59.829 8.624 1.00 52.29 O ATOM 885 CB VAL A 114 28.430 58.415 5.558 1.00 65.61 C ATOM 886 CG1 VAL A 114 28.723 57.279 6.535 1.00 63.46 C ATOM 887 CG2 VAL A 114 27.306 58.047 4.598 1.00 67.38 C ATOM 888 N TYR A 115 30.267 60.445 7.041 1.00 62.83 N ATOM 889 CA TYR A 115 31.294 60.750 7.998 1.00 65.62 C ATOM 890 C TYR A 115 30.821 61.801 9.012 1.00 69.83 C ATOM 891 O TYR A 115 30.814 61.562 10.228 1.00 64.49 O ATOM 892 CB TYR A 115 32.531 61.227 7.272 1.00 67.22 C ATOM 893 CG TYR A 115 33.677 61.417 8.206 1.00 76.50 C ATOM 894 CD1 TYR A 115 34.412 60.319 8.668 1.00 80.03 C ATOM 895 CD2 TYR A 115 34.022 62.685 8.649 1.00 73.27 C ATOM 896 CE1 TYR A 115 35.469 60.487 9.538 1.00 81.41 C ATOM 897 CE2 TYR A 115 35.070 62.864 9.524 1.00 85.68 C ATOM 898 CZ TYR A 115 35.788 61.763 9.968 1.00 86.44 C ATOM 899 OH TYR A 115 36.834 61.961 10.835 1.00 88.49 O ATOM 900 N ASN A 116 30.401 62.952 8.494 1.00 71.64 N ATOM 901 CA ASN A 116 29.921 64.056 9.318 1.00 72.44 C ATOM 902 C ASN A 116 28.750 63.704 10.220 1.00 72.82 C ATOM 903 O ASN A 116 28.647 64.221 11.312 1.00 74.59 O ATOM 904 CB ASN A 116 29.545 65.235 8.437 1.00 74.94 C ATOM 905 CG ASN A 116 30.749 65.877 7.800 1.00 73.10 C ATOM 906 OD1 ASN A 116 30.728 66.216 6.625 1.00 79.46 O ATOM 907 ND2 ASN A 116 31.810 66.043 8.573 1.00 66.31 N ATOM 908 N HIS A 117 27.873 62.823 9.765 1.00 70.88 N ATOM 909 CA HIS A 117 26.789 62.366 10.611 1.00 74.29 C ATOM 910 C HIS A 117 27.198 61.300 11.588 1.00 80.60 C ATOM 911 O HIS A 117 26.472 61.021 12.537 1.00 89.20 O ATOM 912 CB HIS A 117 25.622 61.897 9.759 1.00 73.06 C ATOM 913 CG HIS A 117 24.824 63.032 9.166 1.00 80.50 C ATOM 914 ND1 HIS A 117 23.832 63.652 9.840 1.00 75.00 N ATOM 915 CD2 HIS A 117 24.922 63.674 7.929 1.00 78.39 C ATOM 916 CE1 HIS A 117 23.312 64.619 9.065 1.00 77.93 C ATOM 917 NE2 HIS A 117 23.984 64.633 7.898 1.00 70.97 N ATOM 918 N SER A 118 28.355 60.680 11.374 1.00 85.56 N ATOM 919 CA SER A 118 28.756 59.548 12.208 1.00 80.05 C ATOM 920 C SER A 118 29.826 59.946 13.203 1.00 83.59 C ATOM 921 O SER A 118 29.801 59.489 14.343 1.00 83.66 O ATOM 922 CB SER A 118 29.256 58.385 11.354 1.00 79.81 C ATOM 923 OG SER A 118 28.256 57.915 10.468 1.00 76.84 O ATOM 924 N VAL A 119 30.754 60.802 12.773 1.00 79.90 N ATOM 925 CA VAL A 119 31.882 61.166 13.604 1.00 87.15 C ATOM 926 C VAL A 119 31.578 62.449 14.349 1.00 100.88 C ATOM 927 O VAL A 119 32.121 63.515 14.043 1.00 95.38 O ATOM 928 CB VAL A 119 33.188 61.247 12.803 1.00 93.33 C ATOM 929 CG1 VAL A 119 34.377 61.464 13.731 1.00 94.98 C ATOM 930 CG2 VAL A 119 33.379 59.957 12.031 1.00 94.99 C ATOM 931 N THR A 120 30.686 62.296 15.332 1.00 119.28 N ATOM 932 CA THR A 120 30.202 63.340 16.244 1.00 118.20 C ATOM 933 C THR A 120 31.315 64.241 16.766 1.00 112.85 C ATOM 934 O THR A 120 31.226 65.458 16.692 1.00 112.70 O ATOM 935 CB THR A 120 29.488 62.694 17.455 1.00 127.11 C ATOM 936 OG1 THR A 120 30.346 61.698 18.043 1.00 118.89 O ATOM 937 CG2 THR A 120 28.165 62.032 17.028 1.00 124.57 C ATOM 938 N ASP A 121 32.373 63.631 17.278 1.00 117.23 N ATOM 939 CA ASP A 121 33.465 64.378 17.864 1.00 123.50 C ATOM 940 C ASP A 121 34.766 63.929 17.215 1.00 119.87 C ATOM 941 O ASP A 121 35.386 62.976 17.688 1.00 122.34 O ATOM 942 CB ASP A 121 33.497 64.114 19.369 1.00 134.09 C ATOM 943 CG ASP A 121 34.190 65.214 20.148 1.00 136.35 C ATOM 944 OD1 ASP A 121 35.336 65.576 19.805 1.00 122.11 O ATOM 945 OD2 ASP A 121 33.580 65.708 21.119 1.00 141.06 O ATOM 946 N PRO A 122 35.187 64.607 16.126 1.00 120.35 N ATOM 947 CA PRO A 122 36.358 64.129 15.371 1.00 122.06 C ATOM 948 C PRO A 122 37.653 64.168 16.186 1.00 127.08 C ATOM 949 O PRO A 122 38.742 64.091 15.616 1.00 129.82 O ATOM 950 CB PRO A 122 36.428 65.081 14.162 1.00 114.37 C ATOM 951 CG PRO A 122 35.672 66.296 14.568 1.00 117.18 C ATOM 952 CD PRO A 122 34.637 65.862 15.574 1.00 120.56 C ATOM 953 N GLU A 123 37.518 64.246 17.510 1.00 136.72 N ATOM 954 CA GLU A 123 38.648 64.473 18.412 1.00 143.18 C ATOM 955 C GLU A 123 39.295 63.213 18.978 1.00 138.57 C ATOM 956 O GLU A 123 40.519 63.164 19.111 1.00 144.46 O ATOM 957 CB GLU A 123 38.251 65.419 19.550 1.00 152.95 C ATOM 958 CG GLU A 123 39.204 66.590 19.717 1.00 153.07 C ATOM 959 CD GLU A 123 39.515 67.245 18.386 1.00 156.95 C ATOM 960 OE1 GLU A 123 38.567 67.719 17.719 1.00 159.53 O ATOM 961 OE2 GLU A 123 40.703 67.266 17.998 1.00 153.41 O ATOM 962 N LYS A 124 38.491 62.205 19.312 1.00 130.92 N ATOM 963 CA LYS A 124 39.032 60.913 19.752 1.00 130.53 C ATOM 964 C LYS A 124 39.794 60.173 18.635 1.00 125.97 C ATOM 965 O LYS A 124 39.635 58.967 18.485 1.00 132.10 O ATOM 966 CB LYS A 124 37.928 59.998 20.317 1.00 128.86 C ATOM 967 CG LYS A 124 37.458 60.310 21.732 1.00 132.67 C ATOM 968 CD LYS A 124 35.995 60.750 21.793 1.00 136.53 C ATOM 969 CE LYS A 124 35.765 62.148 21.224 1.00 136.94 C ATOM 970 NZ LYS A 124 36.738 63.163 21.726 1.00 139.69 N ATOM 971 N LEU A 125 40.617 60.885 17.861 1.00 119.99 N ATOM 972 CA LEU A 125 41.421 60.255 16.802 1.00 126.90 C ATOM 973 C LEU A 125 42.905 60.746 16.759 1.00 139.53 C ATOM 974 O LEU A 125 43.443 61.066 15.684 1.00 132.34 O ATOM 975 CB LEU A 125 40.708 60.366 15.430 1.00 128.46 C ATOM 976 CG LEU A 125 39.223 59.950 15.210 1.00 130.27 C ATOM 977 CD1 LEU A 125 38.751 60.304 13.803 1.00 117.63 C ATOM 978 CD2 LEU A 125 38.903 58.479 15.484 1.00 112.25 C ATOM 979 N ASN A 126 43.538 60.790 17.943 1.00 137.85 N ATOM 980 CA ASN A 126 44.980 61.119 18.152 1.00 136.10 C ATOM 981 C ASN A 126 45.439 62.527 17.751 1.00 139.55 C ATOM 982 O ASN A 126 46.619 62.878 17.910 1.00 121.24 O ATOM 983 CB ASN A 126 45.911 60.075 17.508 1.00 137.81 C ATOM 984 CG ASN A 126 45.380 58.661 17.630 1.00 149.55 C ATOM 985 OD1 ASN A 126 45.518 57.857 16.707 1.00 157.87 O ATOM 986 ND2 ASN A 126 44.758 58.352 18.765 1.00 141.82 N ATOM 987 N SER A 132 47.864 64.204 16.275 1.00 101.21 N ATOM 988 CA SER A 132 48.410 65.118 15.262 1.00 122.44 C ATOM 989 C SER A 132 48.519 64.512 13.863 1.00 139.57 C ATOM 990 O SER A 132 48.132 65.172 12.897 1.00 132.12 O ATOM 991 CB SER A 132 49.804 65.628 15.642 1.00 111.03 C ATOM 992 OG SER A 132 50.249 65.054 16.852 1.00 102.89 O ATOM 993 N PRO A 133 49.070 63.272 13.745 1.00 163.86 N ATOM 994 CA PRO A 133 49.451 62.751 12.427 1.00 162.56 C ATOM 995 C PRO A 133 48.349 61.950 11.726 1.00 165.94 C ATOM 996 O PRO A 133 47.515 61.317 12.390 1.00 147.54 O ATOM 997 CB PRO A 133 50.641 61.844 12.754 1.00 163.69 C ATOM 998 CG PRO A 133 50.400 61.385 14.165 1.00 173.13 C ATOM 999 CD PRO A 133 49.352 62.273 14.797 1.00 171.35 C ATOM 1000 N GLU A 134 48.372 61.978 10.391 1.00 175.67 N ATOM 1001 CA GLU A 134 47.368 61.298 9.562 1.00 176.01 C ATOM 1002 C GLU A 134 47.433 59.775 9.657 1.00 181.24 C ATOM 1003 O GLU A 134 47.803 59.085 8.702 1.00 178.60 O ATOM 1004 CB GLU A 134 47.414 61.775 8.101 1.00 163.24 C ATOM 1005 CG GLU A 134 46.285 62.735 7.764 1.00 153.63 C ATOM 1006 CD GLU A 134 44.976 62.290 8.392 1.00 151.75 C ATOM 1007 OE1 GLU A 134 44.453 63.009 9.280 1.00 148.47 O ATOM 1008 OE2 GLU A 134 44.496 61.195 8.027 1.00 145.23 O ATOM 1009 N VAL A 135 47.044 59.277 10.829 1.00 184.91 N ATOM 1010 CA VAL A 135 47.088 57.855 11.157 1.00 171.52 C ATOM 1011 C VAL A 135 45.728 57.188 10.911 1.00 160.47 C ATOM 1012 O VAL A 135 45.456 56.106 11.425 1.00 151.48 O ATOM 1013 CB VAL A 135 47.602 57.622 12.609 1.00 171.02 C ATOM 1014 CG1 VAL A 135 49.040 58.109 12.741 1.00 164.38 C ATOM 1015 CG2 VAL A 135 46.728 58.330 13.642 1.00 166.42 C ATOM 1016 N TYR A 136 44.887 57.850 10.114 1.00 168.20 N ATOM 1017 CA TYR A 136 43.557 57.346 9.744 1.00 167.70 C ATOM 1018 C TYR A 136 43.227 57.592 8.268 1.00 171.31 C ATOM 1019 O TYR A 136 42.400 56.881 7.694 1.00 162.08 O ATOM 1020 CB TYR A 136 42.463 57.968 10.631 1.00 163.81 C ATOM 1021 CG TYR A 136 42.534 57.536 12.079 1.00 156.53 C ATOM 1022 CD1 TYR A 136 41.942 56.341 12.501 1.00 147.41 C ATOM 1023 CD2 TYR A 136 43.201 58.315 13.025 1.00 155.46 C ATOM 1024 CE1 TYR A 136 42.013 55.933 13.826 1.00 142.26 C ATOM 1025 CE2 TYR A 136 43.278 57.917 14.353 1.00 158.31 C ATOM 1026 CZ TYR A 136 42.684 56.727 14.748 1.00 152.05 C ATOM 1027 OH TYR A 136 42.765 56.333 16.065 1.00 142.63 O ATOM 1028 N GLY A 137 43.868 58.603 7.670 1.00 179.02 N ATOM 1029 CA GLY A 137 43.643 58.983 6.267 1.00 172.75 C ATOM 1030 C GLY A 137 42.285 59.626 6.030 1.00 175.73 C ATOM 1031 O GLY A 137 41.326 58.934 5.666 1.00 182.03 O ATOM 1032 N GLU A 138 42.202 60.950 6.217 1.00 168.72 N ATOM 1033 CA GLU A 138 40.911 61.658 6.170 1.00 149.94 C ATOM 1034 C GLU A 138 40.428 62.076 4.766 1.00 142.97 C ATOM 1035 O GLU A 138 39.229 62.006 4.494 1.00 140.45 O ATOM 1036 CB GLU A 138 40.881 62.843 7.154 1.00 146.92 C ATOM 1037 CG GLU A 138 41.414 62.555 8.560 1.00 145.42 C ATOM 1038 CD GLU A 138 40.710 61.415 9.301 1.00 151.96 C ATOM 1039 OE1 GLU A 138 40.850 61.341 10.544 1.00 150.62 O ATOM 1040 OE2 GLU A 138 40.029 60.578 8.667 1.00 145.79 O ATOM 1041 N THR A 139 41.344 62.502 3.888 1.00 141.72 N ATOM 1042 CA THR A 139 40.996 62.856 2.489 1.00 140.28 C ATOM 1043 C THR A 139 41.620 61.926 1.429 1.00 133.27 C ATOM 1044 O THR A 139 41.800 62.324 0.259 1.00 140.99 O ATOM 1045 CB THR A 139 41.361 64.317 2.134 1.00 137.70 C ATOM 1046 OG1 THR A 139 41.200 65.152 3.288 1.00 130.49 O ATOM 1047 CG2 THR A 139 40.485 64.832 0.963 1.00 126.64 C ATOM 1048 N SER A 140 41.927 60.689 1.826 1.00 95.09 N ATOM 1049 CA SER A 140 42.460 59.723 0.878 1.00 92.26 C ATOM 1050 C SER A 140 41.402 59.190 −0.116 1.00 85.18 C ATOM 1051 O SER A 140 41.651 58.227 −0.856 1.00 79.99 O ATOM 1052 CB SER A 140 43.163 58.585 1.623 1.00 98.55 C ATOM 1053 OG SER A 140 42.245 57.814 2.361 1.00 95.96 O ATOM 1054 N PHE A 141 40.237 59.833 −0.153 1.00 74.37 N ATOM 1055 CA PHE A 141 39.186 59.412 −1.053 1.00 66.88 C ATOM 1056 C PHE A 141 39.654 59.341 −2.509 1.00 68.90 C ATOM 1057 O PHE A 141 39.417 58.335 −3.197 1.00 63.96 O ATOM 1058 CB PHE A 141 37.936 60.300 −0.964 1.00 62.39 C ATOM 1059 CG PHE A 141 36.891 59.924 −1.981 1.00 58.27 C ATOM 1060 CD1 PHE A 141 35.852 59.049 −1.640 1.00 52.52 C ATOM 1061 CD2 PHE A 141 36.997 60.368 −3.307 1.00 52.11 C ATOM 1062 CE1 PHE A 141 34.925 58.654 −2.584 1.00 49.74 C ATOM 1063 CE2 PHE A 141 36.070 59.969 −4.256 1.00 52.96 C ATOM 1064 CZ PHE A 141 35.034 59.111 −3.896 1.00 51.28 C ATOM 1065 N ASP A 142 40.279 60.415 −2.985 1.00 65.27 N ATOM 1066 CA ASP A 142 40.682 60.464 −4.387 1.00 71.83 C ATOM 1067 C ASP A 142 41.759 59.429 −4.648 1.00 75.90 C ATOM 1068 O ASP A 142 41.806 58.804 −5.708 1.00 76.65 O ATOM 1069 CB ASP A 142 41.195 61.848 −4.767 1.00 73.81 C ATOM 1070 CG ASP A 142 40.197 62.942 −4.476 1.00 79.61 C ATOM 1071 OD1 ASP A 142 38.997 62.774 −4.791 1.00 85.73 O ATOM 1072 OD2 ASP A 142 40.619 63.979 −3.928 1.00 85.13 O ATOM 1073 N LEU A 143 42.618 59.246 −3.657 1.00 77.46 N ATOM 1074 CA LEU A 143 43.655 58.255 −3.730 1.00 69.74 C ATOM 1075 C LEU A 143 43.051 56.873 −3.902 1.00 69.58 C ATOM 1076 O LEU A 143 43.308 56.200 −4.899 1.00 74.48 O ATOM 1077 CB LEU A 143 44.470 58.306 −2.464 1.00 75.28 C ATOM 1078 CG LEU A 143 45.667 57.389 −2.487 1.00 83.09 C ATOM 1079 CD1 LEU A 143 46.437 57.614 −3.785 1.00 87.47 C ATOM 1080 CD2 LEU A 143 46.494 57.694 −1.248 1.00 78.07 C ATOM 1081 N VAL A 144 42.243 56.451 −2.936 1.00 59.56 N ATOM 1082 CA VAL A 144 41.547 55.183 −3.045 1.00 58.37 C ATOM 1083 C VAL A 144 40.775 55.100 −4.370 1.00 63.24 C ATOM 1084 O VAL A 144 40.594 54.019 −4.936 1.00 63.02 O ATOM 1085 CB VAL A 144 40.533 55.030 −1.911 1.00 62.70 C ATOM 1086 CG1 VAL A 144 39.749 53.734 −2.045 1.00 61.06 C ATOM 1087 CG2 VAL A 144 41.221 55.093 −0.568 1.00 66.26 C ATOM 1088 N ALA A 145 40.299 56.242 −4.858 1.00 60.62 N ATOM 1089 CA ALA A 145 39.489 56.240 −6.056 1.00 58.41 C ATOM 1090 C ALA A 145 40.369 55.827 −7.205 1.00 62.54 C ATOM 1091 O ALA A 145 39.989 54.966 −7.998 1.00 68.65 O ATOM 1092 CB ALA A 145 38.887 57.603 −6.300 1.00 56.03 C ATOM 1093 N GLN A 146 41.558 56.430 −7.270 1.00 65.52 N ATOM 1094 CA GLN A 146 42.573 56.062 −8.256 1.00 70.09 C ATOM 1095 C GLN A 146 42.871 54.565 −8.243 1.00 69.66 C ATOM 1096 O GLN A 146 42.876 53.925 −9.304 1.00 66.21 O ATOM 1097 CB GLN A 146 43.859 56.831 −8.004 1.00 70.66 C ATOM 1098 CG GLN A 146 44.797 56.821 −9.191 1.00 83.13 C ATOM 1099 CD GLN A 146 46.257 56.897 −8.778 1.00 95.99 C ATOM 1100 OE1 GLN A 146 46.597 57.369 −7.680 1.00 94.07 O ATOM 1101 NE2 GLN A 146 47.135 56.419 −9.659 1.00 93.28 N ATOM 1102 N MET A 147 43.092 54.016 −7.042 1.00 62.32 N ATOM 1103 CA MET A 147 43.418 52.609 −6.903 1.00 68.52 C ATOM 1104 C MET A 147 42.310 51.799 −7.513 1.00 71.78 C ATOM 1105 O MET A 147 42.541 50.967 −8.387 1.00 81.04 O ATOM 1106 CB MET A 147 43.640 52.220 −5.437 1.00 69.26 C ATOM 1107 CG MET A 147 44.858 52.887 −4.796 1.00 77.91 C ATOM 1108 SD MET A 147 46.350 52.737 −5.814 1.00 82.45 S ATOM 1109 CE MET A 147 47.267 54.243 −5.477 1.00 76.46 C ATOM 1110 N ILE A 148 41.095 52.088 −7.075 1.00 72.00 N ATOM 1111 CA ILE A 148 39.913 51.412 −7.575 1.00 75.32 C ATOM 1112 C ILE A 148 39.906 51.383 −9.102 1.00 78.42 C ATOM 1113 O ILE A 148 39.558 50.360 −9.694 1.00 82.08 O ATOM 1114 CB ILE A 148 38.627 52.041 −6.988 1.00 72.95 C ATOM 1115 CG1 ILE A 148 38.558 51.733 −5.491 1.00 75.65 C ATOM 1116 CG2 ILE A 148 37.384 51.485 −7.651 1.00 67.59 C ATOM 1117 CD1 ILE A 148 37.411 52.375 −4.751 1.00 75.69 C ATOM 1118 N ASP A 149 40.321 52.488 −9.727 1.00 80.49 N ATOM 1119 CA ASP A 149 40.346 52.583 −11.188 1.00 84.44 C ATOM 1120 C ASP A 149 41.353 51.639 −11.782 1.00 86.80 C ATOM 1121 O ASP A 149 41.106 51.038 −12.827 1.00 96.07 O ATOM 1122 CB ASP A 149 40.679 53.994 −11.664 1.00 88.08 C ATOM 1123 CG ASP A 149 39.444 54.858 −11.845 1.00 95.62 C ATOM 1124 OD1 ASP A 149 38.388 54.345 −12.299 1.00 90.07 O ATOM 1125 OD2 ASP A 149 39.540 56.064 −11.535 1.00 94.34 O ATOM 1126 N GLU A 150 42.484 51.499 −11.107 1.00 83.32 N ATOM 1127 CA GLU A 150 43.599 50.783 −11.683 1.00 79.84 C ATOM 1128 C GLU A 150 43.552 49.270 −11.463 1.00 82.66 C ATOM 1129 O GLU A 150 43.971 48.497 −12.320 1.00 85.41 O ATOM 1130 CB GLU A 150 44.889 51.392 −11.186 1.00 78.07 C ATOM 1131 CG GLU A 150 45.023 52.830 −11.632 1.00 86.71 C ATOM 1132 CD GLU A 150 46.450 53.334 −11.594 1.00 90.75 C ATOM 1133 OE1 GLU A 150 47.370 52.489 −11.675 1.00 81.33 O ATOM 1134 OE2 GLU A 150 46.640 54.578 −11.495 1.00 91.00 O ATOM 1135 N ILE A 151 43.000 48.854 −10.335 1.00 80.30 N ATOM 1136 CA ILE A 151 42.987 47.457 −9.968 1.00 78.21 C ATOM 1137 C ILE A 151 41.649 46.855 −10.367 1.00 79.49 C ATOM 1138 O ILE A 151 40.734 46.789 −9.551 1.00 103.26 O ATOM 1139 CB ILE A 151 43.252 47.318 −8.448 1.00 79.58 C ATOM 1140 CG1 ILE A 151 44.727 47.551 −8.139 1.00 78.52 C ATOM 1141 CG2 ILE A 151 42.908 45.927 −7.929 1.00 83.87 C ATOM 1142 CD1 ILE A 151 45.206 48.953 −8.411 1.00 92.63 C ATOM 1143 N LYS A 152 41.498 46.428 −11.613 1.00 73.87 N ATOM 1144 CA LYS A 152 40.183 45.928 −12.026 1.00 79.84 C ATOM 1145 C LYS A 152 39.725 44.828 −11.090 1.00 78.08 C ATOM 1146 O LYS A 152 40.505 43.954 −10.738 1.00 89.42 O ATOM 1147 CB LYS A 152 40.158 45.484 −13.490 1.00 87.40 C ATOM 1148 CG LYS A 152 39.556 46.513 −14.451 1.00 99.66 C ATOM 1149 CD LYS A 152 40.237 47.884 −14.405 1.00 99.80 C ATOM 1150 CE LYS A 152 39.771 48.800 −15.535 1.00 109.44 C ATOM 1151 NZ LYS A 152 38.307 49.105 −15.531 1.00 113.97 N ATOM 1152 N MET A 153 38.479 44.917 −10.638 1.00 75.81 N ATOM 1153 CA MET A 153 37.910 43.930 −9.724 1.00 76.16 C ATOM 1154 C MET A 153 36.624 43.407 −10.302 1.00 75.82 C ATOM 1155 O MET A 153 36.009 44.064 −11.133 1.00 81.62 O ATOM 1156 CB MET A 153 37.613 44.535 −8.366 1.00 78.27 C ATOM 1157 CG MET A 153 38.787 45.246 −7.728 1.00 77.50 C ATOM 1158 SD MET A 153 38.530 45.394 −5.949 1.00 79.80 S ATOM 1159 CE MET A 153 39.612 46.785 −5.663 1.00 69.58 C ATOM 1160 N THR A 154 36.208 42.232 −9.851 1.00 74.37 N ATOM 1161 CA THR A 154 35.128 41.510 −10.510 1.00 79.19 C ATOM 1162 C THR A 154 34.377 40.732 −9.452 1.00 85.61 C ATOM 1163 O THR A 154 34.867 40.590 −8.329 1.00 88.21 O ATOM 1164 CB THR A 154 35.675 40.461 −11.487 1.00 78.74 C ATOM 1165 OG1 THR A 154 35.996 39.282 −10.744 1.00 90.20 O ATOM 1166 CG2 THR A 154 36.943 40.937 −12.202 1.00 75.24 C ATOM 1167 N ASP A 155 33.220 40.184 −9.823 1.00 90.54 N ATOM 1168 CA ASP A 155 32.384 39.426 −8.887 1.00 89.44 C ATOM 1169 C ASP A 155 33.126 38.269 −8.227 1.00 89.81 C ATOM 1170 O ASP A 155 32.710 37.770 −7.178 1.00 92.24 O ATOM 1171 CB ASP A 155 31.040 38.977 −9.510 1.00 97.59 C ATOM 1172 CG ASP A 155 31.093 38.816 −11.037 1.00 104.80 C ATOM 1173 OD1 ASP A 155 30.539 37.812 −11.537 1.00 92.76 O ATOM 1174 OD2 ASP A 155 31.658 39.690 −11.737 1.00 115.45 O ATOM 1175 N ASP A 156 34.241 37.866 −8.831 1.00 93.09 N ATOM 1176 CA ASP A 156 35.102 36.826 −8.263 1.00 94.08 C ATOM 1177 C ASP A 156 35.807 37.263 −6.976 1.00 94.05 C ATOM 1178 O ASP A 156 35.826 36.521 −5.994 1.00 87.75 O ATOM 1179 CB ASP A 156 36.132 36.351 −9.295 1.00 100.29 C ATOM 1180 CG ASP A 156 35.496 35.565 −10.434 1.00 108.90 C ATOM 1181 OD1 ASP A 156 34.669 34.667 −10.148 1.00 110.14 O ATOM 1182 OD2 ASP A 156 35.817 35.847 −11.612 1.00 104.57 O ATOM 1183 N ASP A 157 36.357 38.475 −6.975 1.00 89.58 N ATOM 1184 CA ASP A 157 37.231 38.917 −5.894 1.00 78.40 C ATOM 1185 C ASP A 157 36.606 39.029 −4.500 1.00 77.75 C ATOM 1186 O ASP A 157 35.400 39.224 −4.358 1.00 74.84 O ATOM 1187 CB ASP A 157 37.870 40.227 −6.278 1.00 73.65 C ATOM 1188 CG ASP A 157 38.750 40.098 −7.475 1.00 76.03 C ATOM 1189 OD1 ASP A 157 39.833 39.511 −7.328 1.00 87.53 O ATOM 1190 OD2 ASP A 157 38.373 40.588 −8.557 1.00 82.24 O ATOM 1191 N LEU A 158 37.453 38.856 −3.486 1.00 77.29 N ATOM 1192 CA LEU A 158 37.154 39.241 −2.114 1.00 74.82 C ATOM 1193 C LEU A 158 38.122 40.331 −1.709 1.00 80.57 C ATOM 1194 O LEU A 158 39.327 40.249 −2.025 1.00 84.12 O ATOM 1195 CB LEU A 158 37.317 38.087 −1.154 1.00 77.72 C ATOM 1196 CG LEU A 158 36.287 36.976 −1.254 1.00 83.38 C ATOM 1197 CD1 LEU A 158 36.897 35.696 −0.712 1.00 76.74 C ATOM 1198 CD2 LEU A 158 35.032 37.356 −0.482 1.00 97.96 C ATOM 1199 N PHE A 159 37.596 41.341 −1.007 1.00 70.34 N ATOM 1200 CA PHE A 159 38.376 42.500 −0.637 1.00 63.38 C ATOM 1201 C PHE A 159 38.449 42.669 0.864 1.00 70.47 C ATOM 1202 O PHE A 159 37.458 42.439 1.567 1.00 77.67 O ATOM 1203 CB PHE A 159 37.808 43.749 −1.279 1.00 62.17 C ATOM 1204 CG PHE A 159 38.444 45.024 −0.797 1.00 59.96 C ATOM 1205 CD1 PHE A 159 39.485 45.610 −1.520 1.00 57.23 C ATOM 1206 CD2 PHE A 159 37.994 45.652 0.374 1.00 55.29 C ATOM 1207 CE1 PHE A 159 40.078 46.797 −1.073 1.00 58.08 C ATOM 1208 CE2 PHE A 159 38.587 46.828 0.826 1.00 56.88 C ATOM 1209 CZ PHE A 159 39.630 47.405 0.101 1.00 54.70 C ATOM 1210 N VAL A 160 39.630 43.083 1.337 1.00 66.97 N ATOM 1211 CA VAL A 160 39.863 43.390 2.744 1.00 64.88 C ATOM 1212 C VAL A 160 40.750 44.634 2.894 1.00 66.72 C ATOM 1213 O VAL A 160 41.773 44.792 2.196 1.00 64.82 O ATOM 1214 CB VAL A 160 40.528 42.209 3.489 1.00 61.80 C ATOM 1215 CG1 VAL A 160 40.844 42.576 4.926 1.00 56.63 C ATOM 1216 CG2 VAL A 160 39.646 40.975 3.471 1.00 71.70 C ATOM 1217 N ASP A 161 40.345 45.507 3.812 1.00 65.83 N ATOM 1218 CA ASP A 161 41.150 46.631 4.232 1.00 66.19 C ATOM 1219 C ASP A 161 41.666 46.242 5.606 1.00 73.22 C ATOM 1220 O ASP A 161 40.882 46.090 6.550 1.00 81.11 O ATOM 1221 CB ASP A 161 40.301 47.905 4.300 1.00 61.21 C ATOM 1222 CG ASP A 161 41.094 49.126 4.779 1.00 70.56 C ATOM 1223 OD1 ASP A 161 42.339 49.136 4.646 1.00 73.71 O ATOM 1224 OD2 ASP A 161 40.476 50.094 5.280 1.00 68.72 O ATOM 1225 N LEU A 162 42.981 46.055 5.710 1.00 74.68 N ATOM 1226 CA LEU A 162 43.622 45.615 6.962 1.00 71.42 C ATOM 1227 C LEU A 162 43.873 46.764 7.922 1.00 71.18 C ATOM 1228 O LEU A 162 44.774 47.585 7.711 1.00 71.46 O ATOM 1229 CB LEU A 162 44.941 44.888 6.678 1.00 72.14 C ATOM 1230 CG LEU A 162 44.824 43.640 5.802 1.00 76.17 C ATOM 1231 CD1 LEU A 162 46.198 43.048 5.517 1.00 72.26 C ATOM 1232 CD2 LEU A 162 43.901 42.621 6.453 1.00 71.92 C ATOM 1233 N GLY A 163 43.100 46.792 9.000 1.00 71.30 N ATOM 1234 CA GLY A 163 43.093 47.937 9.892 1.00 71.82 C ATOM 1235 C GLY A 163 42.232 48.977 9.210 1.00 73.98 C ATOM 1236 O GLY A 163 42.748 49.971 8.680 1.00 72.72 O ATOM 1237 N SER A 164 40.921 48.728 9.217 1.00 68.32 N ATOM 1238 CA SER A 164 39.982 49.472 8.384 1.00 71.28 C ATOM 1239 C SER A 164 39.548 50.837 8.901 1.00 77.43 C ATOM 1240 O SER A 164 38.824 51.553 8.196 1.00 74.68 O ATOM 1241 CB SER A 164 38.754 48.627 8.099 1.00 70.91 C ATOM 1242 OG SER A 164 38.363 47.939 9.255 1.00 76.18 O ATOM 1243 N GLY A 165 40.002 51.198 10.105 1.00 80.99 N ATOM 1244 CA GLY A 165 39.639 52.463 10.742 1.00 78.43 C ATOM 1245 C GLY A 165 38.145 52.540 10.995 1.00 78.78 C ATOM 1246 O GLY A 165 37.533 51.543 11.373 1.00 81.25 O ATOM 1247 N VAL A 166 37.543 53.705 10.746 1.00 79.09 N ATOM 1248 CA VAL A 166 36.093 53.858 10.952 1.00 71.99 C ATOM 1249 C VAL A 166 35.325 53.238 9.790 1.00 71.09 C ATOM 1250 O VAL A 166 34.100 53.216 9.821 1.00 75.79 O ATOM 1251 CB VAL A 166 35.634 55.338 11.180 1.00 73.81 C ATOM 1252 CG1 VAL A 166 36.473 56.037 12.247 1.00 66.36 C ATOM 1253 CG2 VAL A 166 35.637 56.156 9.890 1.00 69.63 C ATOM 1254 N GLY A 167 36.048 52.771 8.761 1.00 65.22 N ATOM 1255 CA GLY A 167 35.463 51.976 7.673 1.00 59.33 C ATOM 1256 C GLY A 167 35.361 52.625 6.299 1.00 62.36 C ATOM 1257 O GLY A 167 34.898 51.986 5.331 1.00 60.88 O ATOM 1258 N GLN A 168 35.808 53.876 6.184 1.00 55.86 N ATOM 1259 CA GLN A 168 35.472 54.655 5.009 1.00 56.81 C ATOM 1260 C GLN A 168 35.977 53.987 3.745 1.00 60.67 C ATOM 1261 O GLN A 168 35.280 53.950 2.732 1.00 67.00 O ATOM 1262 CB GLN A 168 35.946 56.099 5.123 1.00 59.92 C ATOM 1263 CG GLN A 168 37.452 56.289 5.099 1.00 73.04 C ATOM 1264 CD GLN A 168 38.106 56.184 6.460 1.00 73.42 C ATOM 1265 OE1 GLN A 168 37.754 55.345 7.294 1.00 79.82 O ATOM 1266 NE2 GLN A 168 39.080 57.039 6.685 1.00 80.58 N ATOM 1267 N VAL A 169 37.173 53.423 3.806 1.00 59.60 N ATOM 1268 CA VAL A 169 37.735 52.814 2.609 1.00 61.00 C ATOM 1269 C VAL A 169 36.967 51.576 2.173 1.00 60.45 C ATOM 1270 O VAL A 169 36.713 51.392 0.984 1.00 59.15 O ATOM 1271 CB VAL A 169 39.221 52.510 2.771 1.00 65.65 C ATOM 1272 CG1 VAL A 169 39.693 51.597 1.651 1.00 64.42 C ATOM 1273 CG2 VAL A 169 40.013 53.817 2.783 1.00 60.59 C ATOM 1274 N VAL A 170 36.575 50.745 3.133 1.00 59.05 N ATOM 1275 CA VAL A 170 35.748 49.588 2.826 1.00 61.79 C ATOM 1276 C VAL A 170 34.461 50.039 2.150 1.00 67.67 C ATOM 1277 O VAL A 170 34.039 49.459 1.139 1.00 65.28 O ATOM 1278 CB VAL A 170 35.374 48.815 4.092 1.00 64.91 C ATOM 1279 CG1 VAL A 170 34.435 47.655 3.761 1.00 62.25 C ATOM 1280 CG2 VAL A 170 36.628 48.343 4.806 1.00 66.63 C ATOM 1281 N LEU A 171 33.840 51.082 2.705 1.00 68.20 N ATOM 1282 CA LEU A 171 32.592 51.582 2.146 1.00 64.49 C ATOM 1283 C LEU A 171 32.832 52.119 0.737 1.00 62.51 C ATOM 1284 O LEU A 171 32.054 51.843 −0.192 1.00 60.13 O ATOM 1285 CB LEU A 171 31.985 52.661 3.034 1.00 69.75 C ATOM 1286 CG LEU A 171 31.573 52.359 4.480 1.00 69.28 C ATOM 1287 CD1 LEU A 171 31.120 53.641 5.162 1.00 62.60 C ATOM 1288 CD2 LEU A 171 30.466 51.320 4.551 1.00 68.42 C ATOM 1289 N GLN A 172 33.923 52.853 0.559 1.00 53.42 N ATOM 1290 CA GLN A 172 34.209 53.373 −0.772 1.00 57.63 C ATOM 1291 C GLN A 172 34.311 52.226 −1.791 1.00 64.84 C ATOM 1292 O GLN A 172 33.670 52.270 −2.852 1.00 61.73 O ATOM 1293 CB GLN A 172 35.463 54.258 −0.781 1.00 51.11 C ATOM 1294 CG GLN A 172 35.786 54.840 −2.141 1.00 47.82 C ATOM 1295 CD GLN A 172 36.844 55.926 −2.090 1.00 54.28 C ATOM 1296 OE1 GLN A 172 37.351 56.262 −1.034 1.00 54.69 O ATOM 1297 NE2 GLN A 172 37.168 56.496 −3.245 1.00 60.46 N ATOM 1298 N VAL A 173 35.082 51.185 −1.463 1.00 64.98 N ATOM 1299 CA VAL A 173 35.287 50.118 −2.437 1.00 61.88 C ATOM 1300 C VAL A 173 34.001 49.366 −2.683 1.00 60.74 C ATOM 1301 O VAL A 173 33.674 49.066 −3.838 1.00 58.99 O ATOM 1302 CB VAL A 173 36.406 49.133 −2.065 1.00 59.66 C ATOM 1303 CG1 VAL A 173 36.472 48.037 −3.111 1.00 55.29 C ATOM 1304 CG2 VAL A 173 37.741 49.853 −2.008 1.00 58.02 C ATOM 1305 N ALA A 174 33.279 49.068 −1.603 1.00 58.37 N ATOM 1306 CA ALA A 174 32.031 48.312 −1.721 1.00 64.08 C ATOM 1307 C ALA A 174 31.036 49.047 −2.606 1.00 71.83 C ATOM 1308 O ALA A 174 30.258 48.415 −3.333 1.00 73.06 O ATOM 1309 CB ALA A 174 31.423 48.045 −0.359 1.00 62.11 C ATOM 1310 N ALA A 175 31.076 50.384 −2.543 1.00 70.21 N ATOM 1311 CA ALA A 175 30.185 51.217 −3.346 1.00 66.66 C ATOM 1312 C ALA A 175 30.629 51.221 −4.780 1.00 68.06 C ATOM 1313 O ALA A 175 29.815 51.291 −5.673 1.00 81.13 O ATOM 1314 CB ALA A 175 30.152 52.631 −2.812 1.00 70.03 C ATOM 1315 N ALA A 176 31.933 51.115 −4.997 1.00 72.21 N ATOM 1316 CA ALA A 176 32.508 51.275 −6.325 1.00 65.10 C ATOM 1317 C ALA A 176 32.622 49.992 −7.153 1.00 66.15 C ATOM 1318 O ALA A 176 32.628 50.062 −8.377 1.00 69.05 O ATOM 1319 CB ALA A 176 33.857 51.949 −6.213 1.00 60.36 C ATOM 1320 N THR A 177 32.694 48.833 −6.500 1.00 69.60 N ATOM 1321 CA THR A 177 33.010 47.563 −7.190 1.00 69.90 C ATOM 1322 C THR A 177 31.979 46.481 −6.939 1.00 73.92 C ATOM 1323 O THR A 177 31.082 46.622 −6.113 1.00 77.96 O ATOM 1324 CB THR A 177 34.373 46.983 −6.740 1.00 65.08 C ATOM 1325 OG1 THR A 177 34.236 46.360 −5.442 1.00 61.25 O ATOM 1326 CG2 THR A 177 35.417 48.075 −6.687 1.00 54.60 C ATOM 1327 N ASN A 178 32.154 45.370 −7.627 1.00 83.01 N ATOM 1328 CA ASN A 178 31.211 44.278 −7.539 1.00 89.84 C ATOM 1329 C ASN A 178 31.844 43.007 −6.977 1.00 83.77 C ATOM 1330 O ASN A 178 31.465 41.913 −7.358 1.00 88.74 O ATOM 1331 CB ASN A 178 30.621 44.015 −8.926 1.00 100.25 C ATOM 1332 CG ASN A 178 31.693 43.762 −9.971 1.00 113.04 C ATOM 1333 OD1 ASN A 178 32.708 44.470 −10.028 1.00 117.99 O ATOM 1334 ND2 ASN A 178 31.481 42.743 −10.801 1.00 121.14 N ATOM 1335 N CYS A 179 32.805 43.147 −6.073 1.00 76.61 N ATOM 1336 CA CYS A 179 33.328 41.988 −5.353 1.00 80.22 C ATOM 1337 C CYS A 179 32.184 41.233 −4.657 1.00 86.33 C ATOM 1338 O CYS A 179 31.165 41.828 −4.291 1.00 81.49 O ATOM 1339 CB CYS A 179 34.410 42.398 −4.336 1.00 74.17 C ATOM 1340 SG CYS A 179 35.814 43.290 −5.064 1.00 87.83 S ATOM 1341 N LYS A 180 32.359 39.920 −4.491 1.00 90.58 N ATOM 1342 CA LYS A 180 31.393 39.074 −3.799 1.00 87.35 C ATOM 1343 C LYS A 180 31.241 39.537 −2.346 1.00 90.45 C ATOM 1344 O LYS A 180 30.226 39.267 −1.696 1.00 102.13 O ATOM 1345 CB LYS A 180 31.852 37.608 −3.868 1.00 101.07 C ATOM 1346 CG LYS A 180 30.776 36.555 −3.597 1.00 118.50 C ATOM 1347 CD LYS A 180 30.772 36.066 −2.148 1.00 121.62 C ATOM 1348 CE LYS A 180 29.558 35.195 −1.846 1.00 124.55 C ATOM 1349 NZ LYS A 180 29.658 33.825 −2.432 1.00 123.66 N ATOM 1350 N HIS A 181 32.252 40.235 −1.840 1.00 85.17 N ATOM 1351 CA HIS A 181 32.226 40.732 −0.470 1.00 83.61 C ATOM 1352 C HIS A 181 33.421 41.594 −0.142 1.00 84.18 C ATOM 1353 O HIS A 181 34.503 41.410 −0.702 1.00 85.96 O ATOM 1354 CB HIS A 181 32.146 39.573 0.502 1.00 81.88 C ATOM 1355 CG HIS A 181 31.364 39.885 1.728 1.00 82.98 C ATOM 1356 ND1 HIS A 181 30.023 39.888 1.739 1.00 90.45 N ATOM 1357 CD2 HIS A 181 31.774 40.242 3.008 1.00 81.30 C ATOM 1358 CE1 HIS A 181 29.589 40.218 2.976 1.00 92.38 C ATOM 1359 NE2 HIS A 181 30.664 40.431 3.750 1.00 85.50 N ATOM 1360 N HIS A 182 33.232 42.552 0.763 1.00 72.66 N ATOM 1361 CA HIS A 182 34.306 43.447 1.161 1.00 67.31 C ATOM 1362 C HIS A 182 34.389 43.362 2.631 1.00 65.42 C ATOM 1363 O HIS A 182 33.375 43.177 3.288 1.00 71.76 O ATOM 1364 CB HIS A 182 34.006 44.882 0.749 1.00 64.71 C ATOM 1365 CG HIS A 182 33.815 45.072 −0.738 1.00 62.30 C ATOM 1366 ND1 HIS A 182 32.726 44.620 −1.395 1.00 66.02 N ATOM 1367 CD2 HIS A 182 34.612 45.709 −1.691 1.00 63.14 C ATOM 1368 CE1 HIS A 182 32.823 44.949 −2.706 1.00 69.62 C ATOM 1369 NE2 HIS A 182 33.973 45.617 −2.887 1.00 62.86 N ATOM 1370 N TYR A 183 35.587 43.477 3.183 1.00 64.74 N ATOM 1371 CA TYR A 183 35.727 43.330 4.623 1.00 70.95 C ATOM 1372 C TYR A 183 36.624 44.389 5.162 1.00 71.02 C ATOM 1373 O TYR A 183 37.618 44.756 4.535 1.00 76.94 O ATOM 1374 CB TYR A 183 36.360 41.990 4.996 1.00 71.76 C ATOM 1375 CG TYR A 183 35.551 40.786 4.658 1.00 72.85 C ATOM 1376 CD1 TYR A 183 35.628 40.207 3.398 1.00 73.45 C ATOM 1377 CD2 TYR A 183 34.709 40.206 5.604 1.00 80.17 C ATOM 1378 CE1 TYR A 183 34.877 39.084 3.078 1.00 82.01 C ATOM 1379 CE2 TYR A 183 33.961 39.074 5.302 1.00 78.78 C ATOM 1380 CZ TYR A 183 34.047 38.517 4.039 1.00 81.10 C ATOM 1381 OH TYR A 183 33.296 37.405 3.725 1.00 85.27 O ATOM 1382 N GLY A 184 36.298 44.841 6.356 1.00 67.59 N ATOM 1383 CA GLY A 184 37.218 45.649 7.121 1.00 72.28 C ATOM 1384 C GLY A 184 37.441 44.965 8.442 1.00 76.51 C ATOM 1385 O GLY A 184 36.537 44.317 8.985 1.00 77.95 O ATOM 1386 N VAL A 185 38.654 45.090 8.954 1.00 77.16 N ATOM 1387 CA VAL A 185 38.992 44.485 10.226 1.00 76.95 C ATOM 1388 C VAL A 185 39.773 45.525 11.006 1.00 79.94 C ATOM 1389 O VAL A 185 40.722 46.117 10.495 1.00 73.76 O ATOM 1390 CB VAL A 185 39.750 43.143 10.054 1.00 76.17 C ATOM 1391 CG1 VAL A 185 40.991 43.305 9.185 1.00 72.25 C ATOM 1392 CG2 VAL A 185 40.109 42.549 11.407 1.00 79.24 C ATOM 1393 N GLU A 186 39.317 45.766 12.232 1.00 87.17 N ATOM 1394 CA GLU A 186 39.827 46.833 13.089 1.00 90.04 C ATOM 1395 C GLU A 186 39.977 46.305 14.518 1.00 94.44 C ATOM 1396 O GLU A 186 39.079 45.622 15.031 1.00 91.36 O ATOM 1397 CB GLU A 186 38.852 48.011 13.053 1.00 82.54 C ATOM 1398 CG GLU A 186 39.146 49.125 14.032 1.00 78.40 C ATOM 1399 CD GLU A 186 40.495 49.740 13.796 1.00 82.12 C ATOM 1400 OE1 GLU A 186 41.247 49.875 14.771 1.00 85.52 O ATOM 1401 OE2 GLU A 186 40.806 50.076 12.635 1.00 87.86 O ATOM 1402 N LYS A 187 41.105 46.609 15.153 1.00 89.80 N ATOM 1403 CA LYS A 187 41.352 46.092 16.496 1.00 94.87 C ATOM 1404 C LYS A 187 40.882 47.071 17.558 1.00 94.56 C ATOM 1405 O LYS A 187 39.963 46.760 18.304 1.00 107.03 O ATOM 1406 CB LYS A 187 42.814 45.640 16.702 1.00 93.00 C ATOM 1407 CG LYS A 187 43.877 46.716 16.515 1.00 94.75 C ATOM 1408 CD LYS A 187 45.270 46.201 16.839 1.00 94.31 C ATOM 1409 CE LYS A 187 46.271 47.348 16.931 1.00 91.47 C ATOM 1410 NZ LYS A 187 47.470 46.960 17.730 1.00 101.50 N ATOM 1411 N ALA A 188 41.491 48.258 17.591 1.00 97.17 N ATOM 1412 CA ALA A 188 41.142 49.339 18.523 1.00 94.38 C ATOM 1413 C ALA A 188 39.635 49.539 18.622 1.00 105.18 C ATOM 1414 O ALA A 188 38.911 49.461 17.622 1.00 104.53 O ATOM 1415 CB ALA A 188 41.819 50.636 18.114 1.00 80.99 C ATOM 1416 N ASP A 189 39.170 49.807 19.838 1.00 116.25 N ATOM 1417 CA ASP A 189 37.742 49.780 20.132 1.00 111.68 C ATOM 1418 C ASP A 189 36.984 51.015 19.696 1.00 102.49 C ATOM 1419 O ASP A 189 35.860 50.899 19.203 1.00 97.38 O ATOM 1420 CB ASP A 189 37.515 49.500 21.611 1.00 120.96 C ATOM 1421 CG ASP A 189 37.996 48.120 22.005 1.00 138.24 C ATOM 1422 OD1 ASP A 189 37.417 47.132 21.504 1.00 134.67 O ATOM 1423 OD2 ASP A 189 38.959 48.023 22.796 1.00 145.12 O ATOM 1424 N ILE A 190 37.584 52.191 19.866 1.00 94.01 N ATOM 1425 CA ILE A 190 36.853 53.417 19.555 1.00 95.21 C ATOM 1426 C ILE A 190 36.545 53.553 18.042 1.00 98.09 C ATOM 1427 O ILE A 190 35.391 53.808 17.679 1.00 104.71 O ATOM 1428 CB ILE A 190 37.391 54.709 20.276 1.00 95.72 C ATOM 1429 CG1 ILE A 190 38.336 55.536 19.413 1.00 97.11 C ATOM 1430 CG2 ILE A 190 38.012 54.403 21.639 1.00 96.07 C ATOM 1431 CD1 ILE A 190 37.606 56.509 18.525 1.00 97.28 C ATOM 1432 N PRO A 191 37.545 53.337 17.154 1.00 95.75 N ATOM 1433 CA PRO A 191 37.175 53.388 15.738 1.00 83.50 C ATOM 1434 C PRO A 191 36.196 52.285 15.335 1.00 80.28 C ATOM 1435 O PRO A 191 35.314 52.518 14.524 1.00 82.92 O ATOM 1436 CB PRO A 191 38.514 53.237 15.019 1.00 79.71 C ATOM 1437 CG PRO A 191 39.399 52.566 15.996 1.00 83.06 C ATOM 1438 CD PRO A 191 38.997 53.135 17.318 1.00 89.62 C ATOM 1439 N ALA A 192 36.342 51.096 15.906 1.00 85.58 N ATOM 1440 CA ALA A 192 35.379 50.023 15.670 1.00 86.66 C ATOM 1441 C ALA A 192 33.960 50.458 16.052 1.00 89.12 C ATOM 1442 O ALA A 192 32.993 50.136 15.351 1.00 90.45 O ATOM 1443 CB ALA A 192 35.785 48.772 16.428 1.00 82.67 C ATOM 1444 N LYS A 193 33.850 51.190 17.163 1.00 92.07 N ATOM 1445 CA LYS A 193 32.584 51.785 17.579 1.00 96.60 C ATOM 1446 C LYS A 193 32.073 52.721 16.478 1.00 89.98 C ATOM 1447 O LYS A 193 31.023 52.465 15.890 1.00 84.21 O ATOM 1448 CB LYS A 193 32.727 52.508 18.938 1.00 107.12 C ATOM 1449 CG LYS A 193 31.556 53.405 19.364 1.00 114.24 C ATOM 1450 CD LYS A 193 30.205 52.707 19.245 1.00 118.51 C ATOM 1451 CE LYS A 193 29.102 53.509 19.906 1.00 121.55 C ATOM 1452 NZ LYS A 193 28.959 53.117 21.336 1.00 121.19 N ATOM 1453 N TYR A 194 32.824 53.782 16.184 1.00 82.19 N ATOM 1454 CA TYR A 194 32.473 54.668 15.083 1.00 80.44 C ATOM 1455 C TYR A 194 32.048 53.926 13.807 1.00 78.79 C ATOM 1456 O TYR A 194 31.079 54.311 13.159 1.00 82.09 O ATOM 1457 CB TYR A 194 33.606 55.626 14.792 1.00 78.30 C ATOM 1458 CG TYR A 194 33.672 56.789 15.748 1.00 95.29 C ATOM 1459 CD1 TYR A 194 32.502 57.367 16.272 1.00 105.52 C ATOM 1460 CD2 TYR A 194 34.898 57.348 16.105 1.00 103.39 C ATOM 1461 CE1 TYR A 194 32.560 58.452 17.143 1.00 108.82 C ATOM 1462 CE2 TYR A 194 34.968 58.434 16.973 1.00 111.55 C ATOM 1463 CZ TYR A 194 33.803 58.980 17.493 1.00 112.55 C ATOM 1464 OH TYR A 194 33.891 60.054 18.350 1.00 117.17 O ATOM 1465 N ALA A 195 32.735 52.833 13.489 1.00 77.40 N ATOM 1466 CA ALA A 195 32.462 52.074 12.275 1.00 78.17 C ATOM 1467 C ALA A 195 31.048 51.547 12.238 1.00 80.06 C ATOM 1468 O ALA A 195 30.436 51.474 11.167 1.00 83.33 O ATOM 1469 CB ALA A 195 33.454 50.941 12.106 1.00 83.72 C ATOM 1470 N GLU A 196 30.525 51.188 13.406 1.00 78.67 N ATOM 1471 CA GLU A 196 29.134 50.764 13.502 1.00 78.32 C ATOM 1472 C GLU A 196 28.170 51.844 13.049 1.00 78.67 C ATOM 1473 O GLU A 196 27.212 51.567 12.320 1.00 80.48 O ATOM 1474 CB GLU A 196 28.799 50.368 14.915 1.00 78.80 C ATOM 1475 CG GLU A 196 29.237 48.973 15.275 1.00 85.66 C ATOM 1476 CD GLU A 196 28.916 48.657 16.712 1.00 93.43 C ATOM 1477 OE1 GLU A 196 27.783 48.957 17.163 1.00 97.37 O ATOM 1478 OE2 GLU A 196 29.809 48.121 17.392 1.00 98.57 O ATOM 1479 N THR A 197 28.425 53.077 13.472 1.00 74.62 N ATOM 1480 CA THR A 197 27.569 54.168 13.052 1.00 81.13 C ATOM 1481 C THR A 197 27.779 54.476 11.583 1.00 84.28 C ATOM 1482 O THR A 197 26.809 54.650 10.834 1.00 86.91 O ATOM 1483 CB THR A 197 27.789 55.418 13.899 1.00 83.11 C ATOM 1484 OG1 THR A 197 27.570 55.075 15.269 1.00 93.05 O ATOM 1485 CG2 THR A 197 26.807 56.517 13.493 1.00 76.32 C ATOM 1486 N MET A 198 29.047 54.536 11.178 1.00 79.98 N ATOM 1487 CA MET A 198 29.390 54.725 9.776 1.00 77.85 C ATOM 1488 C MET A 198 28.565 53.734 8.972 1.00 75.52 C ATOM 1489 O MET A 198 27.926 54.093 7.985 1.00 68.26 O ATOM 1490 CB MET A 198 30.874 54.466 9.537 1.00 73.04 C ATOM 1491 CG MET A 198 31.814 55.522 10.096 1.00 74.96 C ATOM 1492 SD MET A 198 31.809 57.126 9.268 1.00 77.00 S ATOM 1493 CE MET A 198 32.071 56.689 7.553 1.00 66.32 C ATOM 1494 N ASP A 199 28.552 52.490 9.433 1.00 74.65 N ATOM 1495 CA ASP A 199 27.871 51.448 8.708 1.00 77.70 C ATOM 1496 C ASP A 199 26.396 51.789 8.563 1.00 79.72 C ATOM 1497 O ASP A 199 25.851 51.702 7.465 1.00 76.28 O ATOM 1498 CB ASP A 199 28.077 50.094 9.386 1.00 78.97 C ATOM 1499 CG ASP A 199 27.204 49.010 8.790 1.00 88.12 C ATOM 1500 OD1 ASP A 199 27.083 48.922 7.549 1.00 87.81 O ATOM 1501 OD2 ASP A 199 26.622 48.242 9.577 1.00 100.82 O ATOM 1502 N ARG A 200 25.765 52.192 9.670 1.00 87.18 N ATOM 1503 CA ARG A 200 24.340 52.535 9.674 1.00 81.32 C ATOM 1504 C ARG A 200 24.078 53.727 8.760 1.00 79.40 C ATOM 1505 O ARG A 200 23.300 53.625 7.807 1.00 83.12 O ATOM 1506 CB ARG A 200 23.853 52.814 11.093 1.00 85.62 C ATOM 1507 CG ARG A 200 23.383 51.580 11.844 1.00 97.82 C ATOM 1508 CD ARG A 200 22.765 51.928 13.196 1.00 105.97 C ATOM 1509 NE ARG A 200 23.775 52.086 14.249 1.00 115.59 N ATOM 1510 CZ ARG A 200 24.136 53.246 14.803 1.00 119.27 C ATOM 1511 NH1 ARG A 200 25.071 53.259 15.746 1.00 113.86 N ATOM 1512 NH2 ARG A 200 23.573 54.394 14.430 1.00 116.05 N ATOM 1513 N GLU A 201 24.760 54.838 9.038 1.00 72.33 N ATOM 1514 CA GLU A 201 24.657 56.049 8.238 1.00 72.07 C ATOM 1515 C GLU A 201 24.804 55.780 6.747 1.00 74.85 C ATOM 1516 O GLU A 201 24.030 56.282 5.927 1.00 74.68 O ATOM 1517 CB GLU A 201 25.709 57.061 8.684 1.00 76.50 C ATOM 1518 CG GLU A 201 25.288 57.928 9.867 1.00 82.47 C ATOM 1519 CD GLU A 201 23.890 58.501 9.712 1.00 81.32 C ATOM 1520 OE1 GLU A 201 23.651 59.306 8.775 1.00 77.10 O ATOM 1521 OE2 GLU A 201 23.026 58.120 10.528 1.00 85.88 O ATOM 1522 N PHE A 202 25.793 54.967 6.400 1.00 74.00 N ATOM 1523 CA PHE A 202 26.016 54.623 5.014 1.00 70.89 C ATOM 1524 C PHE A 202 24.817 53.930 4.392 1.00 70.66 C ATOM 1525 O PHE A 202 24.417 54.273 3.277 1.00 72.85 O ATOM 1526 CB PHE A 202 27.266 53.768 4.850 1.00 70.27 C ATOM 1527 CG PHE A 202 27.612 53.466 3.415 1.00 66.51 C ATOM 1528 CD1 PHE A 202 28.081 54.473 2.568 1.00 66.58 C ATOM 1529 CD2 PHE A 202 27.481 52.185 2.917 1.00 61.36 C ATOM 1530 CE1 PHE A 202 28.407 54.210 1.249 1.00 61.69 C ATOM 1531 CE2 PHE A 202 27.812 51.907 1.605 1.00 67.47 C ATOM 1532 CZ PHE A 202 28.275 52.922 0.767 1.00 69.94 C ATOM 1533 N ARG A 203 24.241 52.961 5.099 1.00 67.76 N ATOM 1534 CA ARG A 203 23.141 52.187 4.523 1.00 71.93 C ATOM 1535 C ARG A 203 21.952 53.115 4.275 1.00 76.16 C ATOM 1536 O ARG A 203 21.305 53.054 3.214 1.00 74.63 O ATOM 1537 CB ARG A 203 22.768 50.984 5.406 1.00 78.63 C ATOM 1538 CG ARG A 203 23.937 50.036 5.683 1.00 85.67 C ATOM 1539 CD ARG A 203 23.524 48.606 6.004 1.00 87.89 C ATOM 1540 NE ARG A 203 24.692 47.713 5.999 1.00 100.09 N ATOM 1541 CZ ARG A 203 24.999 46.842 5.030 1.00 102.60 C ATOM 1542 NH1 ARG A 203 24.223 46.710 3.960 1.00 110.73 N ATOM 1543 NH2 ARG A 203 26.088 46.088 5.125 1.00 99.74 N ATOM 1544 N LYS A 204 21.719 54.007 5.242 1.00 70.86 N ATOM 1545 CA LYS A 204 20.617 54.946 5.209 1.00 67.95 C ATOM 1546 C LYS A 204 20.758 55.887 4.017 1.00 72.65 C ATOM 1547 O LYS A 204 19.832 56.033 3.221 1.00 78.31 O ATOM 1548 CB LYS A 204 20.569 55.724 6.531 1.00 72.43 C ATOM 1549 CG LYS A 204 19.670 56.960 6.537 1.00 70.88 C ATOM 1550 CD LYS A 204 19.214 57.314 7.943 1.00 78.67 C ATOM 1551 CE LYS A 204 20.306 57.915 8.827 1.00 89.54 C ATOM 1552 NZ LYS A 204 20.665 59.323 8.472 1.00 92.72 N ATOM 1553 N TRP A 205 21.919 56.520 3.883 1.00 68.14 N ATOM 1554 CA TRP A 205 22.112 57.483 2.799 1.00 69.09 C ATOM 1555 C TRP A 205 22.074 56.860 1.430 1.00 69.66 C ATOM 1556 O TRP A 205 21.606 57.481 0.475 1.00 71.50 O ATOM 1557 CB TRP A 205 23.377 58.315 3.013 1.00 64.43 C ATOM 1558 CG TRP A 205 23.196 59.360 4.095 1.00 65.07 C ATOM 1559 CD1 TRP A 205 23.667 59.328 5.403 1.00 64.70 C ATOM 1560 CD2 TRP A 205 22.441 60.613 3.995 1.00 65.40 C ATOM 1561 NE1 TRP A 205 23.288 60.448 6.086 1.00 64.40 N ATOM 1562 CE2 TRP A 205 22.545 61.258 5.298 1.00 65.08 C ATOM 1563 CE3 TRP A 205 21.706 61.236 2.989 1.00 67.86 C ATOM 1564 CZ2 TRP A 205 21.943 62.476 5.559 1.00 68.19 C ATOM 1565 CZ3 TRP A 205 21.100 62.457 3.267 1.00 65.75 C ATOM 1566 CH2 TRP A 205 21.223 63.067 4.516 1.00 62.40 C ATOM 1567 N MET A 206 22.540 55.621 1.319 1.00 67.52 N ATOM 1568 CA MET A 206 22.519 54.944 0.042 1.00 66.40 C ATOM 1569 C MET A 206 21.081 54.622 −0.371 1.00 70.67 C ATOM 1570 O MET A 206 20.721 54.763 −1.546 1.00 65.42 O ATOM 1571 CB MET A 206 23.394 53.697 0.089 1.00 73.45 C ATOM 1572 CG MET A 206 24.892 53.982 0.085 1.00 75.94 C ATOM 1573 SD MET A 206 25.548 54.539 −1.507 1.00 74.34 S ATOM 1574 CE MET A 206 25.690 53.000 −2.388 1.00 76.03 C ATOM 1575 N LYS A 207 20.259 54.211 0.600 1.00 70.40 N ATOM 1576 CA LYS A 207 18.825 54.031 0.362 1.00 74.40 C ATOM 1577 C LYS A 207 18.175 55.364 −0.058 1.00 74.47 C ATOM 1578 O LYS A 207 17.433 55.447 −1.041 1.00 74.19 O ATOM 1579 CB LYS A 207 18.139 53.434 1.600 1.00 82.03 C ATOM 1580 CG LYS A 207 18.309 51.921 1.759 1.00 94.80 C ATOM 1581 CD LYS A 207 17.658 51.162 0.590 1.00 114.67 C ATOM 1582 CE LYS A 207 17.933 49.661 0.591 1.00 114.07 C ATOM 1583 NZ LYS A 207 17.471 48.987 1.841 1.00 127.27 N ATOM 1584 N TRP A 208 18.510 56.416 0.672 1.00 70.71 N ATOM 1585 CA TRP A 208 18.005 57.747 0.391 1.00 64.65 C ATOM 1586 C TRP A 208 18.231 58.198 −1.018 1.00 65.14 C ATOM 1587 O TRP A 208 17.323 58.747 −1.629 1.00 69.42 O ATOM 1588 CB TRP A 208 18.620 58.729 1.360 1.00 59.99 C ATOM 1589 CG TRP A 208 17.912 60.053 1.415 1.00 64.54 C ATOM 1590 CD1 TRP A 208 16.930 60.460 2.322 1.00 68.30 C ATOM 1591 CD2 TRP A 208 18.134 61.214 0.557 1.00 65.09 C ATOM 1592 NE1 TRP A 208 16.550 61.754 2.085 1.00 62.01 N ATOM 1593 CE2 TRP A 208 17.229 62.266 1.046 1.00 62.98 C ATOM 1594 CE3 TRP A 208 18.962 61.484 −0.526 1.00 66.11 C ATOM 1595 CZ2 TRP A 208 17.165 63.515 0.449 1.00 63.76 C ATOM 1596 CZ3 TRP A 208 18.889 62.751 −1.117 1.00 65.40 C ATOM 1597 CH2 TRP A 208 18.007 63.738 −0.641 1.00 63.65 C ATOM 1598 N TYR A 209 19.436 57.997 −1.552 1.00 67.05 N ATOM 1599 CA TYR A 209 19.703 58.401 −2.939 1.00 66.05 C ATOM 1600 C TYR A 209 19.297 57.264 −3.879 1.00 65.33 C ATOM 1601 O TYR A 209 19.403 57.395 −5.097 1.00 61.49 O ATOM 1602 CB TYR A 209 21.184 58.745 −3.170 1.00 64.71 C ATOM 1603 CG TYR A 209 21.754 59.954 −2.431 1.00 59.31 C ATOM 1604 CD1 TYR A 209 21.784 61.233 −3.030 1.00 54.95 C ATOM 1605 CD2 TYR A 209 22.328 59.809 −1.171 1.00 54.84 C ATOM 1606 CE1 TYR A 209 22.322 62.334 −2.370 1.00 47.80 C ATOM 1607 CE2 TYR A 209 22.879 60.892 −0.506 1.00 55.91 C ATOM 1608 CZ TYR A 209 22.879 62.151 −1.104 1.00 55.61 C ATOM 1609 OH TYR A 209 23.431 63.209 −0.405 1.00 55.70 O ATOM 1610 N GLY A 210 18.843 56.146 −3.312 1.00 60.23 N ATOM 1611 CA GLY A 210 18.481 54.987 −4.122 1.00 65.87 C ATOM 1612 C GLY A 210 19.613 54.429 −4.977 1.00 70.56 C ATOM 1613 O GLY A 210 19.420 54.158 −6.171 1.00 75.15 O ATOM 1614 N LYS A 211 20.790 54.265 −4.363 1.00 66.61 N ATOM 1615 CA LYS A 211 21.985 53.746 −5.030 1.00 61.73 C ATOM 1616 C LYS A 211 22.485 52.449 −4.388 1.00 72.08 C ATOM 1617 O LYS A 211 22.490 52.308 −3.155 1.00 72.86 O ATOM 1618 CB LYS A 211 23.091 54.786 −5.024 1.00 58.67 C ATOM 1619 CG LYS A 211 22.816 56.006 −5.876 1.00 61.14 C ATOM 1620 CD LYS A 211 22.777 55.642 −7.352 1.00 63.41 C ATOM 1621 CE LYS A 211 23.023 56.851 −8.234 1.00 70.83 C ATOM 1622 NZ LYS A 211 22.544 56.658 −9.632 1.00 75.54 N ATOM 1623 N LYS A 212 22.923 51.526 −5.244 1.00 76.77 N ATOM 1624 CA LYS A 212 23.275 50.143 −4.897 1.00 79.60 C ATOM 1625 C LYS A 212 24.704 50.006 −4.315 1.00 75.41 C ATOM 1626 O LYS A 212 25.584 50.805 −4.617 1.00 76.61 O ATOM 1627 CB LYS A 212 23.131 49.327 −6.194 1.00 88.57 C ATOM 1628 CG LYS A 212 23.537 47.863 −6.177 1.00 98.58 C ATOM 1629 CD LYS A 212 24.229 47.523 −7.496 1.00 109.02 C ATOM 1630 CE LYS A 212 23.870 46.135 −8.018 1.00 119.03 C ATOM 1631 NZ LYS A 212 23.861 45.070 −6.971 1.00 121.53 N ATOM 1632 N HIS A 213 24.941 48.985 −3.499 1.00 77.91 N ATOM 1633 CA HIS A 213 26.305 48.670 −3.070 1.00 81.34 C ATOM 1634 C HIS A 213 26.562 47.195 −2.902 1.00 85.40 C ATOM 1635 O HIS A 213 25.668 46.433 −2.531 1.00 91.73 O ATOM 1636 CB HIS A 213 26.626 49.370 −1.770 1.00 76.11 C ATOM 1637 CG HIS A 213 25.940 48.762 −0.583 1.00 80.49 C ATOM 1638 ND1 HIS A 213 24.793 49.248 −0.089 1.00 85.45 N ATOM 1639 CD2 HIS A 213 26.269 47.663 0.196 1.00 76.28 C ATOM 1640 CE1 HIS A 213 24.414 48.508 0.966 1.00 78.97 C ATOM 1641 NE2 HIS A 213 25.320 47.542 1.139 1.00 80.59 N ATOM 1642 N ALA A 214 27.809 46.791 −3.129 1.00 81.48 N ATOM 1643 CA ALA A 214 28.210 45.403 −2.990 1.00 74.53 C ATOM 1644 C ALA A 214 28.201 44.993 −1.521 1.00 78.64 C ATOM 1645 O ALA A 214 28.235 45.840 −0.641 1.00 81.11 O ATOM 1646 CB ALA A 214 29.576 45.198 −3.602 1.00 73.03 C ATOM 1647 N GLU A 215 28.132 43.698 −1.241 1.00 84.45 N ATOM 1648 CA GLU A 215 28.042 43.279 0.149 1.00 83.99 C ATOM 1649 C GLU A 215 29.357 43.526 0.882 1.00 82.89 C ATOM 1650 O GLU A 215 30.441 43.389 0.308 1.00 87.85 O ATOM 1651 CB GLU A 215 27.603 41.834 0.260 1.00 86.85 C ATOM 1652 CG GLU A 215 26.580 41.640 1.367 1.00 110.26 C ATOM 1653 CD GLU A 215 26.453 40.188 1.800 1.00 124.02 C ATOM 1654 OE1 GLU A 215 26.139 39.947 2.991 1.00 117.32 O ATOM 1655 OE2 GLU A 215 26.682 39.288 0.955 1.00 130.15 O ATOM 1656 N TYR A 216 29.255 43.932 2.140 1.00 76.50 N ATOM 1657 CA TYR A 216 30.431 44.288 2.917 1.00 72.59 C ATOM 1658 C TYR A 216 30.143 44.086 4.376 1.00 68.58 C ATOM 1659 O TYR A 216 28.992 44.062 4.775 1.00 67.75 O ATOM 1660 CB TYR A 216 30.825 45.759 2.690 1.00 78.90 C ATOM 1661 CG TYR A 216 29.886 46.781 3.341 1.00 77.86 C ATOM 1662 CD1 TYR A 216 29.967 47.065 4.708 1.00 75.78 C ATOM 1663 CD2 TYR A 216 28.933 47.468 2.583 1.00 73.30 C ATOM 1664 CE1 TYR A 216 29.118 47.980 5.304 1.00 75.06 C ATOM 1665 CE2 TYR A 216 28.079 48.393 3.169 1.00 72.90 C ATOM 1666 CZ TYR A 216 28.175 48.643 4.533 1.00 77.30 C ATOM 1667 OH TYR A 216 27.327 49.556 5.137 1.00 74.00 O ATOM 1668 N THR A 217 31.206 44.005 5.169 1.00 71.36 N ATOM 1669 CA THR A 217 31.114 43.756 6.596 1.00 74.84 C ATOM 1670 C THR A 217 32.256 44.458 7.276 1.00 75.33 C ATOM 1671 O THR A 217 33.399 44.404 6.811 1.00 84.27 O ATOM 1672 CB THR A 217 31.247 42.255 6.933 1.00 76.03 C ATOM 1673 OG1 THR A 217 30.233 41.521 6.248 1.00 82.07 O ATOM 1674 CG2 THR A 217 31.087 42.023 8.417 1.00 73.41 C ATOM 1675 N LEU A 218 31.940 45.102 8.387 1.00 72.31 N ATOM 1676 CA LEU A 218 32.960 45.672 9.237 1.00 76.23 C ATOM 1677 C LEU A 218 33.058 44.843 10.494 1.00 81.64 C ATOM 1678 O LEU A 218 32.044 44.505 11.090 1.00 91.00 O ATOM 1679 CB LEU A 218 32.629 47.123 9.564 1.00 67.31 C ATOM 1680 CG LEU A 218 32.495 47.961 8.297 1.00 65.78 C ATOM 1681 CD1 LEU A 218 32.045 49.364 8.654 1.00 70.98 C ATOM 1682 CD2 LEU A 218 33.818 47.989 7.532 1.00 67.36 C ATOM 1683 N GLU A 219 34.282 44.515 10.891 1.00 85.84 N ATOM 1684 CA GLU A 219 34.505 43.572 11.967 1.00 80.16 C ATOM 1685 C GLU A 219 35.474 44.086 12.990 1.00 85.71 C ATOM 1686 O GLU A 219 36.393 44.844 12.672 1.00 95.14 O ATOM 1687 CB GLU A 219 35.055 42.268 11.410 1.00 79.55 C ATOM 1688 CG GLU A 219 34.114 41.539 10.473 1.00 81.66 C ATOM 1689 CD GLU A 219 34.699 40.233 9.983 1.00 89.09 C ATOM 1690 OE1 GLU A 219 35.555 39.652 10.698 1.00 86.41 O ATOM 1691 OE2 GLU A 219 34.293 39.788 8.885 1.00 91.38 O ATOM 1692 N ARG A 220 35.274 43.651 14.227 1.00 91.74 N ATOM 1693 CA ARG A 220 36.263 43.856 15.263 1.00 95.98 C ATOM 1694 C ARG A 220 37.223 42.666 15.202 1.00 94.65 C ATOM 1695 O ARG A 220 36.787 41.523 15.067 1.00 101.89 O ATOM 1696 CB ARG A 220 35.588 43.973 16.627 1.00 100.86 C ATOM 1697 CG ARG A 220 36.074 45.164 17.431 1.00 111.47 C ATOM 1698 CD ARG A 220 35.676 45.045 18.889 1.00 125.97 C ATOM 1699 NE ARG A 220 36.821 45.319 19.753 1.00 139.80 N ATOM 1700 CZ ARG A 220 37.738 44.415 20.105 1.00 151.82 C ATOM 1701 NH1 ARG A 220 37.657 43.158 19.678 1.00 150.89 N ATOM 1702 NH2 ARG A 220 38.745 44.769 20.894 1.00 156.60 N ATOM 1703 N GLY A 221 38.525 42.931 15.251 1.00 88.77 N ATOM 1704 CA GLY A 221 39.508 41.858 15.159 1.00 83.01 C ATOM 1705 C GLY A 221 40.921 42.348 14.954 1.00 86.58 C ATOM 1706 O GLY A 221 41.136 43.505 14.604 1.00 87.88 O ATOM 1707 N ASP A 222 41.884 41.465 15.209 1.00 89.53 N ATOM 1708 CA ASP A 222 43.289 41.717 14.906 1.00 83.58 C ATOM 1709 C ASP A 222 43.596 40.874 13.690 1.00 91.87 C ATOM 1710 O ASP A 222 43.194 39.707 13.626 1.00 98.81 O ATOM 1711 CB ASP A 222 44.182 41.311 16.072 1.00 79.28 C ATOM 1712 CG ASP A 222 45.624 41.777 15.906 1.00 87.66 C ATOM 1713 OD1 ASP A 222 46.226 41.542 14.834 1.00 89.79 O ATOM 1714 OD2 ASP A 222 46.174 42.373 16.864 1.00 91.36 O ATOM 1715 N PHE A 223 44.283 41.458 12.710 1.00 91.82 N ATOM 1716 CA PHE A 223 44.526 40.731 11.467 1.00 85.01 C ATOM 1717 C PHE A 223 45.759 39.814 11.532 1.00 84.32 C ATOM 1718 O PHE A 223 46.111 39.131 10.571 1.00 92.47 O ATOM 1719 CB PHE A 223 44.506 41.660 10.240 1.00 78.39 C ATOM 1720 CG PHE A 223 45.510 42.769 10.276 1.00 74.44 C ATOM 1721 CD1 PHE A 223 46.882 42.504 10.211 1.00 78.35 C ATOM 1722 CD2 PHE A 223 45.086 44.084 10.312 1.00 73.69 C ATOM 1723 CE1 PHE A 223 47.809 43.538 10.222 1.00 72.35 C ATOM 1724 CE2 PHE A 223 46.002 45.128 10.321 1.00 74.59 C ATOM 1725 CZ PHE A 223 47.366 44.857 10.279 1.00 73.76 C ATOM 1726 N LEU A 224 46.398 39.801 12.689 1.00 82.96 N ATOM 1727 CA LEU A 224 47.440 38.834 12.972 1.00 86.73 C ATOM 1728 C LEU A 224 46.870 37.647 13.760 1.00 88.46 C ATOM 1729 O LEU A 224 47.506 36.603 13.837 1.00 88.87 O ATOM 1730 CB LEU A 224 48.605 39.506 13.708 1.00 78.66 C ATOM 1731 CG LEU A 224 49.084 40.808 13.049 1.00 75.02 C ATOM 1732 CD1 LEU A 224 50.067 41.570 13.927 1.00 67.80 C ATOM 1733 CD2 LEU A 224 49.688 40.517 11.679 1.00 74.77 C ATOM 1734 N SER A 225 45.661 37.803 14.309 1.00 92.27 N ATOM 1735 CA SER A 225 44.995 36.735 15.065 1.00 95.35 C ATOM 1736 C SER A 225 44.915 35.460 14.245 1.00 103.93 C ATOM 1737 O SER A 225 44.696 35.505 13.031 1.00 108.59 O ATOM 1738 CB SER A 225 43.587 37.140 15.495 1.00 90.35 C ATOM 1739 OG SER A 225 42.655 36.879 14.460 1.00 96.73 O ATOM 1740 N GLU A 226 45.079 34.330 14.928 1.00 112.30 N ATOM 1741 CA GLU A 226 45.109 33.012 14.298 1.00 107.86 C ATOM 1742 C GLU A 226 44.072 32.866 13.186 1.00 103.68 C ATOM 1743 O GLU A 226 44.403 32.449 12.075 1.00 101.39 O ATOM 1744 CB GLU A 226 44.927 31.915 15.359 1.00 110.45 C ATOM 1745 CG GLU A 226 45.447 30.544 14.942 1.00 107.60 C ATOM 1746 CD GLU A 226 46.897 30.588 14.476 1.00 112.49 C ATOM 1747 OE1 GLU A 226 47.234 29.876 13.499 1.00 110.29 O ATOM 1748 OE2 GLU A 226 47.698 31.347 15.073 1.00 105.39 O ATOM 1749 N GLU A 227 42.833 33.243 13.493 1.00 102.88 N ATOM 1750 CA GLU A 227 41.721 33.171 12.551 1.00 105.95 C ATOM 1751 C GLU A 227 42.018 33.862 11.218 1.00 108.94 C ATOM 1752 O GLU A 227 41.635 33.361 10.152 1.00 108.40 O ATOM 1753 CB GLU A 227 40.470 33.783 13.178 1.00 111.01 C ATOM 1754 CG GLU A 227 39.167 33.307 12.547 1.00 116.65 C ATOM 1755 CD GLU A 227 38.115 34.405 12.454 1.00 120.83 C ATOM 1756 OE1 GLU A 227 38.033 35.247 13.376 1.00 115.49 O ATOM 1757 OE2 GLU A 227 37.366 34.433 11.451 1.00 116.37 O ATOM 1758 N TRP A 228 42.709 35.001 11.279 1.00 100.39 N ATOM 1759 CA TRP A 228 42.984 35.784 10.080 1.00 96.82 C ATOM 1760 C TRP A 228 43.972 35.183 9.122 1.00 100.77 C ATOM 1761 O TRP A 228 43.929 35.500 7.925 1.00 103.75 O ATOM 1762 CB TRP A 228 43.292 37.241 10.421 1.00 98.86 C ATOM 1763 CG TRP A 228 42.000 38.008 10.507 1.00 99.38 C ATOM 1764 CD1 TRP A 228 41.259 38.309 11.648 1.00 98.45 C ATOM 1765 CD2 TRP A 228 41.193 38.512 9.388 1.00 97.28 C ATOM 1766 NE1 TRP A 228 40.098 38.968 11.320 1.00 95.93 N ATOM 1767 CE2 TRP A 228 39.997 39.126 9.986 1.00 94.92 C ATOM 1768 CE3 TRP A 228 41.345 38.536 8.005 1.00 90.35 C ATOM 1769 CZ2 TRP A 228 39.023 39.734 9.216 1.00 89.84 C ATOM 1770 CZ3 TRP A 228 40.349 39.146 7.238 1.00 89.51 C ATOM 1771 CH2 TRP A 228 39.214 39.726 7.832 1.00 92.12 C ATOM 1772 N ARG A 229 44.848 34.306 9.615 1.00 92.23 N ATOM 1773 CA ARG A 229 45.781 33.590 8.740 1.00 90.74 C ATOM 1774 C ARG A 229 45.028 32.974 7.574 1.00 90.55 C ATOM 1775 O ARG A 229 45.372 33.183 6.412 1.00 87.29 O ATOM 1776 CB ARG A 229 46.513 32.470 9.482 1.00 95.77 C ATOM 1777 CG ARG A 229 47.408 32.903 10.626 1.00 99.63 C ATOM 1778 CD ARG A 229 48.472 31.858 10.920 1.00 94.73 C ATOM 1779 NE ARG A 229 49.456 32.361 11.881 1.00 99.55 N ATOM 1780 CZ ARG A 229 50.683 32.773 11.564 1.00 100.25 C ATOM 1781 NH1 ARG A 229 51.093 32.727 10.295 1.00 98.38 N ATOM 1782 NH2 ARG A 229 51.503 33.226 12.518 1.00 89.44 N ATOM 1783 N GLU A 230 43.987 32.214 7.891 1.00 101.10 N ATOM 1784 CA GLU A 230 43.221 31.527 6.862 1.00 105.37 C ATOM 1785 C GLU A 230 42.596 32.544 5.895 1.00 103.20 C ATOM 1786 O GLU A 230 42.808 32.474 4.676 1.00 91.76 O ATOM 1787 CB GLU A 230 42.172 30.610 7.511 1.00 115.36 C ATOM 1788 CG GLU A 230 41.288 29.833 6.537 1.00 134.43 C ATOM 1789 CD GLU A 230 42.061 29.187 5.396 1.00 149.04 C ATOM 1790 OE1 GLU A 230 42.999 28.401 5.667 1.00 162.60 O ATOM 1791 OE2 GLU A 230 41.724 29.465 4.223 1.00 151.39 O ATOM 1792 N ARG A 231 41.869 33.506 6.466 1.00 98.29 N ATOM 1793 CA ARG A 231 41.124 34.511 5.706 1.00 87.49 C ATOM 1794 C ARG A 231 42.003 35.267 4.725 1.00 85.14 C ATOM 1795 O ARG A 231 41.687 35.342 3.530 1.00 83.14 O ATOM 1796 CB ARG A 231 40.421 35.458 6.663 1.00 81.13 C ATOM 1797 CG ARG A 231 39.553 34.694 7.643 1.00 87.95 C ATOM 1798 CD ARG A 231 38.765 35.591 8.566 1.00 84.41 C ATOM 1799 NE ARG A 231 37.724 36.311 7.848 1.00 89.10 N ATOM 1800 CZ ARG A 231 36.902 37.181 8.421 1.00 95.85 C ATOM 1801 NH1 ARG A 231 35.984 37.796 7.695 1.00 94.79 N ATOM 1802 NH2 ARG A 231 37.000 37.438 9.722 1.00 98.43 N ATOM 1803 N ILE A 232 43.122 35.796 5.221 1.00 76.17 N ATOM 1804 CA ILE A 232 44.094 36.465 4.353 1.00 74.31 C ATOM 1805 C ILE A 232 44.519 35.614 3.144 1.00 77.97 C ATOM 1806 O ILE A 232 44.642 36.119 2.014 1.00 77.48 O ATOM 1807 CB ILE A 232 45.356 36.856 5.120 1.00 65.87 C ATOM 1808 CG1 ILE A 232 45.083 38.082 5.988 1.00 70.21 C ATOM 1809 CG2 ILE A 232 46.495 37.088 4.137 1.00 62.82 C ATOM 1810 CD1 ILE A 232 46.268 38.583 6.797 1.00 73.21 C ATOM 1811 N ALA A 233 44.753 34.329 3.396 1.00 76.27 N ATOM 1812 CA ALA A 233 45.180 33.427 2.356 1.00 78.91 C ATOM 1813 C ALA A 233 44.069 33.336 1.325 1.00 82.57 C ATOM 1814 O ALA A 233 44.329 33.245 0.112 1.00 80.07 O ATOM 1815 CB ALA A 233 45.503 32.071 2.949 1.00 83.76 C ATOM 1816 N ASN A 234 42.833 33.423 1.814 1.00 82.31 N ATOM 1817 CA ASN A 234 41.664 33.408 0.942 1.00 93.16 C ATOM 1818 C ASN A 234 41.291 34.711 0.233 1.00 95.55 C ATOM 1819 O ASN A 234 40.514 34.688 −0.725 1.00 95.59 O ATOM 1820 CB ASN A 234 40.446 32.864 1.682 1.00 102.99 C ATOM 1821 CG ASN A 234 39.945 31.579 1.074 1.00 112.30 C ATOM 1822 OD1 ASN A 234 38.871 31.546 0.471 1.00 114.54 O ATOM 1823 ND2 ASN A 234 40.742 30.516 1.190 1.00 115.09 N ATOM 1824 N THR A 235 41.824 35.841 0.693 1.00 85.97 N ATOM 1825 CA THR A 235 41.472 37.118 0.091 1.00 80.68 C ATOM 1826 C THR A 235 42.267 37.349 −1.188 1.00 76.85 C ATOM 1827 O THR A 235 43.464 37.079 −1.200 1.00 84.40 O ATOM 1828 CB THR A 235 41.718 38.262 1.080 1.00 84.75 C ATOM 1829 OG1 THR A 235 40.953 38.030 2.273 1.00 87.00 O ATOM 1830 CG2 THR A 235 41.319 39.593 0.461 1.00 82.34 C ATOM 1831 N SER A 236 41.607 37.836 −2.248 1.00 69.34 N ATOM 1832 CA SER A 236 42.277 38.166 −3.535 1.00 62.74 C ATOM 1833 C SER A 236 42.670 39.610 −3.695 1.00 69.52 C ATOM 1834 O SER A 236 43.537 39.904 −4.500 1.00 78.65 O ATOM 1835 CB SER A 236 41.419 37.803 −4.747 1.00 65.24 C ATOM 1836 OG SER A 236 40.140 38.425 −4.729 1.00 63.39 O ATOM 1837 N VAL A 237 42.005 40.524 −2.981 1.00 74.37 N ATOM 1838 CA VAL A 237 42.435 41.926 −3.001 1.00 72.39 C ATOM 1839 C VAL A 237 42.599 42.519 −1.607 1.00 71.71 C ATOM 1840 O VAL A 237 41.633 42.630 −0.853 1.00 72.83 O ATOM 1841 CB VAL A 237 41.508 42.832 −3.821 1.00 69.05 C ATOM 1842 CG1 VAL A 237 42.000 44.266 −3.733 1.00 65.31 C ATOM 1843 CG2 VAL A 237 41.477 42.395 −5.273 1.00 68.43 C ATOM 1844 N ILE A 238 43.826 42.920 −1.292 1.00 59.87 N ATOM 1845 CA ILE A 238 44.144 43.423 0.013 1.00 62.06 C ATOM 1846 C ILE A 238 44.604 44.851 −0.146 1.00 65.99 C ATOM 1847 O ILE A 238 45.508 45.149 −0.956 1.00 64.28 O ATOM 1848 CB ILE A 238 45.338 42.674 0.664 1.00 70.91 C ATOM 1849 CG1 ILE A 238 45.200 41.144 0.574 1.00 67.92 C ATOM 1850 CG2 ILE A 238 45.569 43.180 2.094 1.00 66.60 C ATOM 1851 CD1 ILE A 238 44.536 40.501 1.765 1.00 66.86 C ATOM 1852 N PHE A 239 44.009 45.731 0.647 1.00 60.98 N ATOM 1853 CA PHE A 239 44.499 47.089 0.742 1.00 64.21 C ATOM 1854 C PHE A 239 45.021 47.209 2.156 1.00 66.93 C ATOM 1855 O PHE A 239 44.313 46.835 3.116 1.00 69.94 O ATOM 1856 CB PHE A 239 43.363 48.095 0.534 1.00 66.27 C ATOM 1857 CG PHE A 239 43.062 48.433 −0.903 1.00 62.56 C ATOM 1858 CD1 PHE A 239 43.556 47.685 −1.948 1.00 62.93 C ATOM 1859 CD2 PHE A 239 42.243 49.523 −1.199 1.00 65.85 C ATOM 1860 CE1 PHE A 239 43.256 48.018 −3.261 1.00 65.90 C ATOM 1861 CE2 PHE A 239 41.938 49.859 −2.504 1.00 60.25 C ATOM 1862 CZ PHE A 239 42.443 49.106 −3.539 1.00 62.56 C ATOM 1863 N VAL A 240 46.246 47.714 2.286 1.00 59.96 N ATOM 1864 CA VAL A 240 46.854 47.908 3.588 1.00 60.72 C ATOM 1865 C VAL A 240 47.709 49.158 3.562 1.00 65.75 C ATOM 1866 O VAL A 240 48.636 49.289 2.750 1.00 68.65 O ATOM 1867 CB VAL A 240 47.678 46.672 4.041 1.00 68.66 C ATOM 1868 CG1 VAL A 240 48.798 46.336 3.050 1.00 66.92 C ATOM 1869 CG2 VAL A 240 48.248 46.874 5.441 1.00 71.13 C ATOM 1870 N ASN A 241 47.370 50.091 4.437 1.00 65.21 N ATOM 1871 CA ASN A 241 48.103 51.322 4.515 1.00 73.76 C ATOM 1872 C ASN A 241 49.145 51.152 5.575 1.00 77.63 C ATOM 1873 O ASN A 241 48.932 51.503 6.737 1.00 82.65 O ATOM 1874 CB ASN A 241 47.182 52.481 4.865 1.00 79.15 C ATOM 1875 CG ASN A 241 47.893 53.819 4.817 1.00 76.98 C ATOM 1876 OD1 ASN A 241 49.095 53.907 4.537 1.00 78.09 O ATOM 1877 ND2 ASN A 241 47.154 54.868 5.091 1.00 75.81 N ATOM 1878 N ASN A 242 50.273 50.595 5.167 1.00 80.92 N ATOM 1879 CA ASN A 242 51.285 50.154 6.112 1.00 83.82 C ATOM 1880 C ASN A 242 52.369 51.182 6.397 1.00 91.28 C ATOM 1881 O ASN A 242 53.425 50.837 6.921 1.00 97.75 O ATOM 1882 CB ASN A 242 51.917 48.869 5.601 1.00 79.06 C ATOM 1883 CG ASN A 242 52.501 49.018 4.209 1.00 82.85 C ATOM 1884 OD1 ASN A 242 51.955 49.722 3.355 1.00 83.64 O ATOM 1885 ND2 ASN A 242 53.599 48.326 3.963 1.00 79.84 N ATOM 1886 N PHE A 243 52.100 52.449 6.088 1.00 96.93 N ATOM 1887 CA PHE A 243 53.166 53.449 6.060 1.00 91.16 C ATOM 1888 C PHE A 243 53.981 53.497 7.331 1.00 84.26 C ATOM 1889 O PHE A 243 55.167 53.771 7.287 1.00 97.41 O ATOM 1890 CB PHE A 243 52.648 54.851 5.735 1.00 100.61 C ATOM 1891 CG PHE A 243 53.698 55.739 5.123 1.00 112.53 C ATOM 1892 CD1 PHE A 243 53.944 55.706 3.748 1.00 116.76 C ATOM 1893 CD2 PHE A 243 54.467 56.586 5.916 1.00 116.64 C ATOM 1894 CE1 PHE A 243 54.923 56.506 3.175 1.00 112.49 C ATOM 1895 CE2 PHE A 243 55.446 57.392 5.346 1.00 122.36 C ATOM 1896 CZ PHE A 243 55.674 57.352 3.975 1.00 121.65 C ATOM 1897 N ALA A 244 53.340 53.231 8.458 1.00 84.23 N ATOM 1898 CA ALA A 244 53.988 53.358 9.752 1.00 81.19 C ATOM 1899 C ALA A 244 53.910 52.034 10.498 1.00 86.84 C ATOM 1900 O ALA A 244 53.786 52.002 11.719 1.00 91.27 O ATOM 1901 CB ALA A 244 53.333 54.472 10.565 1.00 76.22 C ATOM 1902 N PHE A 245 53.980 50.933 9.768 1.00 82.29 N ATOM 1903 CA PHE A 245 53.969 49.644 10.419 1.00 81.54 C ATOM 1904 C PHE A 245 55.315 49.223 11.017 1.00 92.59 C ATOM 1905 O PHE A 245 55.369 48.598 12.091 1.00 96.05 O ATOM 1906 CB PHE A 245 53.459 48.598 9.460 1.00 77.62 C ATOM 1907 CG PHE A 245 51.977 48.496 9.444 1.00 77.21 C ATOM 1908 CD1 PHE A 245 51.224 49.126 10.425 1.00 73.56 C ATOM 1909 CD2 PHE A 245 51.329 47.732 8.485 1.00 75.18 C ATOM 1910 CE1 PHE A 245 49.849 49.016 10.441 1.00 66.30 C ATOM 1911 CE2 PHE A 245 49.954 47.612 8.497 1.00 72.44 C ATOM 1912 CZ PHE A 245 49.215 48.251 9.480 1.00 70.19 C ATOM 1913 N GLY A 246 56.397 49.553 10.323 1.00 88.31 N ATOM 1914 CA GLY A 246 57.720 49.148 10.769 1.00 104.15 C ATOM 1915 C GLY A 246 58.009 47.650 10.702 1.00 114.88 C ATOM 1916 O GLY A 246 57.209 46.864 10.184 1.00 117.90 O ATOM 1917 N PRO A 247 59.155 47.242 11.263 1.00 119.54 N ATOM 1918 CA PRO A 247 59.771 45.922 11.083 1.00 110.66 C ATOM 1919 C PRO A 247 58.935 44.706 11.557 1.00 104.35 C ATOM 1920 O PRO A 247 58.721 43.758 10.795 1.00 93.41 O ATOM 1921 CB PRO A 247 61.064 46.048 11.892 1.00 121.22 C ATOM 1922 CG PRO A 247 60.761 47.082 12.935 1.00 120.00 C ATOM 1923 CD PRO A 247 59.906 48.075 12.223 1.00 116.71 C ATOM 1924 N GLU A 248 58.483 44.737 12.804 1.00 104.43 N ATOM 1925 CA GLU A 248 57.789 43.610 13.406 1.00 101.94 C ATOM 1926 C GLU A 248 56.602 43.187 12.547 1.00 102.25 C ATOM 1927 O GLU A 248 56.507 42.027 12.132 1.00 104.07 O ATOM 1928 CB GLU A 248 57.351 43.981 14.834 1.00 116.76 C ATOM 1929 CG GLU A 248 56.506 42.945 15.565 1.00 128.47 C ATOM 1930 CD GLU A 248 57.289 41.715 15.991 1.00 134.27 C ATOM 1931 OE1 GLU A 248 57.667 41.637 17.184 1.00 148.32 O ATOM 1932 OE2 GLU A 248 57.525 40.826 15.140 1.00 116.67 O ATOM 1933 N VAL A 249 55.721 44.141 12.246 1.00 101.69 N ATOM 1934 CA VAL A 249 54.461 43.821 11.570 1.00 90.03 C ATOM 1935 C VAL A 249 54.629 43.524 10.072 1.00 87.59 C ATOM 1936 O VAL A 249 53.930 42.651 9.533 1.00 81.23 O ATOM 1937 CB VAL A 249 53.361 44.871 11.824 1.00 90.91 C ATOM 1938 CG1 VAL A 249 52.001 44.271 11.514 1.00 88.95 C ATOM 1939 CG2 VAL A 249 53.387 45.338 13.275 1.00 94.02 C ATOM 1940 N ASP A 250 55.556 44.214 9.399 1.00 80.30 N ATOM 1941 CA ASP A 250 55.762 43.921 7.980 1.00 92.01 C ATOM 1942 C ASP A 250 56.070 42.442 7.824 1.00 90.39 C ATOM 1943 O ASP A 250 55.456 41.765 6.997 1.00 91.57 O ATOM 1944 CB ASP A 250 56.820 44.821 7.311 1.00 100.33 C ATOM 1945 CG ASP A 250 56.221 46.145 6.718 1.00 115.15 C ATOM 1946 OD1 ASP A 250 54.983 46.294 6.515 1.00 100.86 O ATOM 1947 OD2 ASP A 250 57.021 47.064 6.440 1.00 127.45 O ATOM 1948 N HIS A 251 56.965 41.939 8.677 1.00 92.37 N ATOM 1949 CA HIS A 251 57.337 40.526 8.675 1.00 89.23 C ATOM 1950 C HIS A 251 56.168 39.585 8.857 1.00 86.01 C ATOM 1951 O HIS A 251 55.937 38.695 8.023 1.00 71.69 O ATOM 1952 CB HIS A 251 58.417 40.220 9.713 1.00 102.40 C ATOM 1953 CG HIS A 251 58.768 38.750 9.780 1.00 107.09 C ATOM 1954 ND1 HIS A 251 59.610 38.162 8.894 1.00 99.42 N ATOM 1955 CD2 HIS A 251 58.301 37.737 10.619 1.00 94.57 C ATOM 1956 CE1 HIS A 251 59.693 36.853 9.170 1.00 101.35 C ATOM 1957 NE2 HIS A 251 58.886 36.592 10.223 1.00 105.98 N ATOM 1958 N GLN A 252 55.413 39.744 9.939 1.00 79.08 N ATOM 1959 CA GLN A 252 54.230 38.904 10.080 1.00 85.53 C ATOM 1960 C GLN A 252 53.340 38.946 8.838 1.00 86.38 C ATOM 1961 O GLN A 252 52.762 37.931 8.458 1.00 88.19 O ATOM 1962 CB GLN A 252 53.420 39.294 11.296 1.00 91.20 C ATOM 1963 CG GLN A 252 54.018 38.846 12.606 1.00 94.95 C ATOM 1964 CD GLN A 252 53.759 39.875 13.677 1.00 105.26 C ATOM 1965 OE1 GLN A 252 54.354 40.956 13.664 1.00 112.73 O ATOM 1966 NE2 GLN A 252 52.854 39.561 14.601 1.00 98.21 N ATOM 1967 N LEU A 253 53.224 40.112 8.203 1.00 83.15 N ATOM 1968 CA LEU A 253 52.339 40.216 7.051 1.00 82.16 C ATOM 1969 C LEU A 253 52.866 39.393 5.879 1.00 85.70 C ATOM 1970 O LEU A 253 52.129 38.553 5.333 1.00 83.65 O ATOM 1971 CB LEU A 253 52.070 41.669 6.669 1.00 81.14 C ATOM 1972 CG LEU A 253 51.089 42.423 7.584 1.00 77.64 C ATOM 1973 CD1 LEU A 253 51.024 43.903 7.231 1.00 70.63 C ATOM 1974 CD2 LEU A 253 49.701 41.813 7.560 1.00 66.81 C ATOM 1975 N LYS A 254 54.139 39.613 5.528 1.00 77.46 N ATOM 1976 CA LYS A 254 54.835 38.806 4.521 1.00 72.77 C ATOM 1977 C LYS A 254 54.535 37.329 4.715 1.00 75.93 C ATOM 1978 O LYS A 254 54.145 36.646 3.773 1.00 77.92 O ATOM 1979 CB LYS A 254 56.334 39.021 4.618 1.00 73.27 C ATOM 1980 CG LYS A 254 56.864 40.250 3.911 1.00 73.79 C ATOM 1981 CD LYS A 254 57.926 40.918 4.759 1.00 66.02 C ATOM 1982 CE LYS A 254 58.956 41.588 3.868 1.00 71.80 C ATOM 1983 NZ LYS A 254 59.755 42.632 4.588 1.00 78.03 N ATOM 1984 N GLU A 255 54.715 36.852 5.950 1.00 82.22 N ATOM 1985 CA GLU A 255 54.346 35.490 6.363 1.00 83.05 C ATOM 1986 C GLU A 255 52.959 35.155 5.806 1.00 80.41 C ATOM 1987 O GLU A 255 52.839 34.311 4.924 1.00 80.58 O ATOM 1988 CB GLU A 255 54.353 35.403 7.896 1.00 93.30 C ATOM 1989 CG GLU A 255 54.815 34.108 8.560 1.00 96.35 C ATOM 1990 CD GLU A 255 54.771 34.220 10.096 1.00 113.99 C ATOM 1991 OE1 GLU A 255 53.893 33.578 10.726 1.00 106.03 O ATOM 1992 OE2 GLU A 255 55.594 34.976 10.685 1.00 115.14 O ATOM 1993 N ARG A 256 51.932 35.873 6.266 1.00 77.67 N ATOM 1994 CA ARG A 256 50.548 35.588 5.898 1.00 71.97 C ATOM 1995 C ARG A 256 50.222 35.750 4.409 1.00 76.40 C ATOM 1996 O ARG A 256 49.360 35.036 3.884 1.00 84.88 O ATOM 1997 CB ARG A 256 49.596 36.425 6.740 1.00 78.24 C ATOM 1998 CG ARG A 256 49.994 36.529 8.200 1.00 77.55 C ATOM 1999 CD ARG A 256 48.773 36.470 9.104 1.00 78.62 C ATOM 2000 NE ARG A 256 49.067 36.438 10.545 1.00 85.56 N ATOM 2001 CZ ARG A 256 50.279 36.448 11.121 1.00 87.62 C ATOM 2002 NH1 ARG A 256 51.414 36.485 10.418 1.00 77.74 N ATOM 2003 NH2 ARG A 256 50.353 36.421 12.443 1.00 86.74 N ATOM 2004 N PHE A 257 50.905 36.664 3.718 1.00 73.22 N ATOM 2005 CA PHE A 257 50.728 36.796 2.255 1.00 78.10 C ATOM 2006 C PHE A 257 51.159 35.592 1.426 1.00 83.07 C ATOM 2007 O PHE A 257 50.536 35.295 0.403 1.00 78.15 O ATOM 2008 CB PHE A 257 51.451 38.025 1.708 1.00 79.16 C ATOM 2009 CG PHE A 257 50.939 39.317 2.259 1.00 79.37 C ATOM 2010 CD1 PHE A 257 49.616 39.430 2.696 1.00 77.14 C ATOM 2011 CD2 PHE A 257 51.771 40.423 2.342 1.00 74.50 C ATOM 2012 CE1 PHE A 257 49.145 40.615 3.220 1.00 70.14 C ATOM 2013 CE2 PHE A 257 51.305 41.613 2.863 1.00 72.45 C ATOM 2014 CZ PHE A 257 49.992 41.708 3.303 1.00 71.11 C ATOM 2015 N ALA A 258 52.231 34.923 1.870 1.00 92.89 N ATOM 2016 CA ALA A 258 52.832 33.773 1.172 1.00 81.33 C ATOM 2017 C ALA A 258 51.848 32.643 0.886 1.00 81.73 C ATOM 2018 O ALA A 258 52.020 31.897 −0.078 1.00 80.67 O ATOM 2019 CB ALA A 258 54.021 33.258 1.939 1.00 76.19 C ATOM 2020 N ASN A 259 50.802 32.538 1.699 1.00 78.90 N ATOM 2021 CA ASN A 259 49.730 31.588 1.423 1.00 80.88 C ATOM 2022 C ASN A 259 48.630 32.057 0.447 1.00 87.04 C ATOM 2023 O ASN A 259 47.599 31.407 0.332 1.00 93.73 O ATOM 2024 CB ASN A 259 49.101 31.146 2.738 1.00 78.57 C ATOM 2025 CG ASN A 259 50.090 30.439 3.635 1.00 85.97 C ATOM 2026 OD1 ASN A 259 50.919 29.655 3.161 1.00 89.90 O ATOM 2027 ND2 ASN A 259 50.020 30.713 4.933 1.00 76.58 N ATOM 2028 N MET A 260 48.817 33.165 −0.259 1.00 82.66 N ATOM 2029 CA MET A 260 47.717 33.662 −1.087 1.00 83.28 C ATOM 2030 C MET A 260 47.657 32.957 −2.439 1.00 77.61 C ATOM 2031 O MET A 260 48.689 32.576 −2.978 1.00 77.27 O ATOM 2032 CB MET A 260 47.792 35.180 −1.255 1.00 82.22 C ATOM 2033 CG MET A 260 47.371 35.949 −0.007 1.00 84.81 C ATOM 2034 SD MET A 260 47.742 37.707 −0.165 1.00 79.19 S ATOM 2035 CE MET A 260 46.453 38.161 −1.326 1.00 79.49 C ATOM 2036 N LYS A 261 46.449 32.791 −2.980 1.00 74.07 N ATOM 2037 CA LYS A 261 46.267 32.136 −4.276 1.00 71.32 C ATOM 2038 C LYS A 261 47.006 32.882 −5.361 1.00 70.01 C ATOM 2039 O LYS A 261 47.399 34.017 −5.179 1.00 71.48 O ATOM 2040 CB LYS A 261 44.793 32.032 −4.653 1.00 76.26 C ATOM 2041 CG LYS A 261 43.975 31.021 −3.861 1.00 76.65 C ATOM 2042 CD LYS A 261 42.777 30.595 −4.700 1.00 89.36 C ATOM 2043 CE LYS A 261 41.869 29.635 −3.951 1.00 108.27 C ATOM 2044 NZ LYS A 261 41.240 30.268 −2.754 1.00 108.68 N ATOM 2045 N GLU A 262 47.222 32.226 −6.488 1.00 83.47 N ATOM 2046 CA GLU A 262 47.913 32.842 −7.612 1.00 85.74 C ATOM 2047 C GLU A 262 47.026 33.985 −8.084 1.00 84.11 C ATOM 2048 O GLU A 262 45.810 33.840 −8.093 1.00 83.67 O ATOM 2049 CB GLU A 262 48.109 31.793 −8.713 1.00 84.45 C ATOM 2050 CG GLU A 262 48.875 32.264 −9.939 1.00 85.74 C ATOM 2051 CD GLU A 262 50.374 32.239 −9.739 1.00 95.36 C ATOM 2052 OE1 GLU A 262 51.083 32.638 −10.694 1.00 96.16 O ATOM 2053 OE2 GLU A 262 50.833 31.828 −8.640 1.00 93.25 O ATOM 2054 N GLY A 263 47.615 35.127 −8.432 1.00 83.08 N ATOM 2055 CA GLY A 263 46.824 36.276 −8.908 1.00 83.61 C ATOM 2056 C GLY A 263 46.428 37.328 −7.864 1.00 84.36 C ATOM 2057 O GLY A 263 46.303 38.516 −8.192 1.00 84.95 O ATOM 2058 N GLY A 264 46.218 36.891 −6.619 1.00 71.91 N ATOM 2059 CA GLY A 264 45.983 37.772 −5.478 1.00 67.16 C ATOM 2060 C GLY A 264 46.798 39.056 −5.476 1.00 75.62 C ATOM 2061 O GLY A 264 47.974 39.076 −5.891 1.00 81.64 O ATOM 2062 N ARG A 265 46.174 40.138 −5.010 1.00 73.30 N ATOM 2063 CA ARG A 265 46.805 41.448 −5.063 1.00 68.43 C ATOM 2064 C ARG A 265 46.910 42.115 −3.713 1.00 68.78 C ATOM 2065 O ARG A 265 46.018 41.967 −2.866 1.00 67.38 O ATOM 2066 CB ARG A 265 46.124 42.344 −6.084 1.00 63.05 C ATOM 2067 CG ARG A 265 46.530 41.955 −7.493 1.00 68.85 C ATOM 2068 CD ARG A 265 45.498 42.346 −8.531 1.00 70.35 C ATOM 2069 NE ARG A 265 44.181 41.746 −8.304 1.00 69.00 N ATOM 2070 CZ ARG A 265 43.086 42.100 −8.976 1.00 71.57 C ATOM 2071 NH1 ARG A 265 41.919 41.523 −8.708 1.00 73.68 N ATOM 2072 NH2 ARG A 265 43.151 43.050 −9.911 1.00 68.87 N ATOM 2073 N ILE A 266 48.031 42.808 −3.511 1.00 62.17 N ATOM 2074 CA ILE A 266 48.220 43.587 −2.312 1.00 67.87 C ATOM 2075 C ILE A 266 48.617 44.965 −2.735 1.00 66.84 C ATOM 2076 O ILE A 266 49.578 45.125 −3.488 1.00 70.97 O ATOM 2077 CB ILE A 266 49.301 43.022 −1.368 1.00 73.16 C ATOM 2078 CG1 ILE A 266 48.930 41.615 −0.884 1.00 80.20 C ATOM 2079 CG2 ILE A 266 49.482 43.920 −0.153 1.00 57.48 C ATOM 2080 CD1 ILE A 266 49.641 40.496 −1.623 1.00 82.57 C ATOM 2081 N VAL A 267 47.858 45.954 −2.260 1.00 63.56 N ATOM 2082 CA VAL A 267 48.154 47.353 −2.554 1.00 63.38 C ATOM 2083 C VAL A 267 48.492 48.045 −1.247 1.00 60.36 C ATOM 2084 O VAL A 267 47.738 47.934 −0.266 1.00 60.44 O ATOM 2085 CB VAL A 267 46.990 48.081 −3.277 1.00 63.01 C ATOM 2086 CG1 VAL A 267 47.518 49.333 −3.935 1.00 63.15 C ATOM 2087 CG2 VAL A 267 46.352 47.203 −4.347 1.00 60.18 C ATOM 2088 N SER A 268 49.625 48.741 −1.225 1.00 55.69 N ATOM 2089 CA SER A 268 50.149 49.271 0.035 1.00 65.22 C ATOM 2090 C SER A 268 50.967 50.547 −0.172 1.00 67.01 C ATOM 2091 O SER A 268 51.286 50.899 −1.311 1.00 68.27 O ATOM 2092 CB SER A 268 51.032 48.215 0.722 1.00 63.06 C ATOM 2093 OG SER A 268 52.241 48.000 −0.013 1.00 68.63 O ATOM 2094 N SER A 269 51.338 51.203 0.926 1.00 58.34 N ATOM 2095 CA SER A 269 52.183 52.371 0.843 1.00 68.44 C ATOM 2096 C SER A 269 53.670 52.046 0.911 1.00 72.99 C ATOM 2097 O SER A 269 54.476 52.706 0.267 1.00 79.05 O ATOM 2098 CB SER A 269 51.796 53.445 1.867 1.00 68.10 C ATOM 2099 OG SER A 269 51.375 52.882 3.086 1.00 79.47 O ATOM 2100 N LYS A 270 54.037 51.048 1.702 1.00 83.43 N ATOM 2101 CA LYS A 270 55.411 50.551 1.721 1.00 74.37 C ATOM 2102 C LYS A 270 55.411 49.207 1.026 1.00 71.57 C ATOM 2103 O LYS A 270 54.481 48.412 1.216 1.00 72.40 O ATOM 2104 CB LYS A 270 55.872 50.348 3.144 1.00 77.09 C ATOM 2105 CG LYS A 270 56.210 51.589 3.942 1.00 88.61 C ATOM 2106 CD LYS A 270 56.145 51.165 5.401 1.00 100.62 C ATOM 2107 CE LYS A 270 57.248 51.730 6.277 1.00 99.29 C ATOM 2108 NZ LYS A 270 57.169 51.054 7.608 1.00 95.61 N ATOM 2109 N PRO A 271 56.452 48.925 0.227 1.00 74.05 N ATOM 2110 CA PRO A 271 56.487 47.657 −0.526 1.00 73.03 C ATOM 2111 C PRO A 271 56.926 46.477 0.332 1.00 71.55 C ATOM 2112 O PRO A 271 57.813 46.623 1.176 1.00 76.37 O ATOM 2113 CB PRO A 271 57.510 47.933 −1.622 1.00 66.95 C ATOM 2114 CG PRO A 271 58.383 49.005 −1.087 1.00 61.72 C ATOM 2115 CD PRO A 271 57.678 49.713 0.037 1.00 70.25 C ATOM 2116 N PHE A 272 56.286 45.331 0.126 1.00 74.60 N ATOM 2117 CA PHE A 272 56.579 44.101 0.884 1.00 79.36 C ATOM 2118 C PHE A 272 57.683 43.236 0.267 1.00 78.78 C ATOM 2119 O PHE A 272 58.247 42.374 0.940 1.00 88.26 O ATOM 2120 CB PHE A 272 55.313 43.266 1.065 1.00 75.80 C ATOM 2121 CG PHE A 272 54.323 43.869 2.016 1.00 72.99 C ATOM 2122 CD1 PHE A 272 54.587 43.913 3.385 1.00 77.12 C ATOM 2123 CD2 PHE A 272 53.123 44.381 1.549 1.00 67.95 C ATOM 2124 CE1 PHE A 272 53.668 44.461 4.273 1.00 76.42 C ATOM 2125 CE2 PHE A 272 52.205 44.934 2.426 1.00 72.57 C ATOM 2126 CZ PHE A 272 52.475 44.974 3.790 1.00 76.37 C ATOM 2127 N ALA A 273 57.946 43.452 −1.017 1.00 72.38 N ATOM 2128 CA ALA A 273 59.139 42.972 −1.693 1.00 77.08 C ATOM 2129 C ALA A 273 59.902 44.207 −2.165 1.00 86.24 C ATOM 2130 O ALA A 273 59.525 45.320 −1.806 1.00 94.43 O ATOM 2131 CB ALA A 273 58.748 42.113 −2.877 1.00 75.37 C ATOM 2132 N PRO A 274 61.009 44.029 −2.917 1.00 87.28 N ATOM 2133 CA PRO A 274 61.476 45.192 −3.671 1.00 83.11 C ATOM 2134 C PRO A 274 61.212 45.054 −5.172 1.00 86.23 C ATOM 2135 O PRO A 274 60.788 43.992 −5.655 1.00 81.75 O ATOM 2136 CB PRO A 274 62.984 45.246 −3.360 1.00 83.48 C ATOM 2137 CG PRO A 274 63.263 44.092 −2.438 1.00 80.53 C ATOM 2138 CD PRO A 274 62.127 43.125 −2.615 1.00 81.08 C ATOM 2139 N LEU A 275 61.460 46.138 −5.896 1.00 92.68 N ATOM 2140 CA LEU A 275 60.977 46.294 −7.265 1.00 96.21 C ATOM 2141 C LEU A 275 62.109 45.889 −8.165 1.00 104.05 C ATOM 2142 O LEU A 275 61.927 45.252 −9.207 1.00 111.38 O ATOM 2143 CB LEU A 275 60.604 47.766 −7.518 1.00 102.16 C ATOM 2144 CG LEU A 275 60.146 48.676 −6.355 1.00 99.00 C ATOM 2145 CD1 LEU A 275 61.299 49.288 −5.554 1.00 97.37 C ATOM 2146 CD2 LEU A 275 59.260 49.776 −6.899 1.00 95.05 C ATOM 2147 N ASN A 276 63.291 46.282 −7.713 1.00 116.62 N ATOM 2148 CA ASN A 276 64.572 45.917 −8.264 1.00 118.47 C ATOM 2149 C ASN A 276 64.965 44.545 −7.734 1.00 122.85 C ATOM 2150 O ASN A 276 66.014 44.406 −7.105 1.00 132.56 O ATOM 2151 CB ASN A 276 65.582 46.945 −7.762 1.00 122.86 C ATOM 2152 CG ASN A 276 65.536 47.117 −6.238 1.00 126.43 C ATOM 2153 OD1 ASN A 276 66.498 46.777 −5.548 1.00 124.54 O ATOM 2154 ND2 ASN A 276 64.413 47.629 −5.708 1.00 118.18 N ATOM 2155 N PHE A 277 64.124 43.536 −7.953 1.00 119.24 N ATOM 2156 CA PHE A 277 64.356 42.228 −7.336 1.00 116.43 C ATOM 2157 C PHE A 277 64.536 41.181 −8.400 1.00 120.15 C ATOM 2158 O PHE A 277 63.625 40.916 −9.189 1.00 128.01 O ATOM 2159 CB PHE A 277 63.204 41.840 −6.399 1.00 111.79 C ATOM 2160 CG PHE A 277 63.403 40.527 −5.676 1.00 103.66 C ATOM 2161 CD1 PHE A 277 63.943 40.496 −4.386 1.00 101.29 C ATOM 2162 CD2 PHE A 277 63.018 39.319 −6.266 1.00 99.39 C ATOM 2163 CE1 PHE A 277 64.111 39.291 −3.707 1.00 100.57 C ATOM 2164 CE2 PHE A 277 63.193 38.109 −5.598 1.00 96.91 C ATOM 2165 CZ PHE A 277 63.736 38.094 −4.317 1.00 97.30 C ATOM 2166 N ARG A 278 65.728 40.601 −8.426 1.00 124.56 N ATOM 2167 CA ARG A 278 66.004 39.477 −9.307 1.00 126.70 C ATOM 2168 C ARG A 278 66.438 38.290 −8.452 1.00 121.84 C ATOM 2169 O ARG A 278 67.041 38.453 −7.392 1.00 121.55 O ATOM 2170 CB ARG A 278 67.029 39.845 −10.385 1.00 126.73 C ATOM 2171 CG ARG A 278 66.548 39.521 −11.796 1.00 131.90 C ATOM 2172 CD ARG A 278 67.402 40.194 −12.857 1.00 133.10 C ATOM 2173 NE ARG A 278 68.738 39.604 −12.941 1.00 137.61 N ATOM 2174 CZ ARG A 278 69.754 40.125 −13.624 1.00 141.09 C ATOM 2175 NH1 ARG A 278 69.605 41.264 −14.294 1.00 140.17 N ATOM 2176 NH2 ARG A 278 70.928 39.507 −13.633 1.00 137.68 N ATOM 2177 N ILE A 279 66.114 37.096 −8.923 1.00 122.33 N ATOM 2178 CA ILE A 279 66.071 35.906 −8.075 1.00 125.51 C ATOM 2179 C ILE A 279 67.389 35.089 −8.063 1.00 130.87 C ATOM 2180 O ILE A 279 67.877 34.668 −9.117 1.00 125.28 O ATOM 2181 CB ILE A 279 64.806 35.076 −8.449 1.00 125.87 C ATOM 2182 CG1 ILE A 279 64.662 33.819 −7.582 1.00 113.99 C ATOM 2183 CG2 ILE A 279 64.726 34.812 −9.962 1.00 118.73 C ATOM 2184 CD1 ILE A 279 63.357 33.092 −7.826 1.00 119.42 C ATOM 2185 N ASN A 280 67.959 34.883 −6.870 1.00 130.24 N ATOM 2186 CA ASN A 280 69.268 34.211 −6.721 1.00 126.71 C ATOM 2187 C ASN A 280 69.393 33.238 −5.535 1.00 126.97 C ATOM 2188 O ASN A 280 68.535 33.194 −4.649 1.00 128.92 O ATOM 2189 CB ASN A 280 70.413 35.245 −6.681 1.00 112.90 C ATOM 2190 CG ASN A 280 70.547 35.937 −5.323 1.00 115.54 C ATOM 2191 OD1 ASN A 280 70.438 35.307 −4.255 1.00 106.95 O ATOM 2192 ND2 ASN A 280 70.807 37.244 −5.359 1.00 106.51 N ATOM 2193 N SER A 281 70.496 32.492 −5.527 1.00 129.43 N ATOM 2194 CA SER A 281 70.835 31.512 −4.487 1.00 127.94 C ATOM 2195 C SER A 281 70.382 31.806 −3.042 1.00 127.16 C ATOM 2196 O SER A 281 69.821 30.922 −2.389 1.00 122.92 O ATOM 2197 CB SER A 281 72.342 31.227 −4.513 1.00 129.67 C ATOM 2198 OG SER A 281 73.087 32.434 −4.453 1.00 126.91 O ATOM 2199 N ARG A 282 70.620 33.024 −2.541 1.00 123.28 N ATOM 2200 CA ARG A 282 70.362 33.317 −1.112 1.00 123.24 C ATOM 2201 C ARG A 282 69.130 34.167 −0.798 1.00 119.87 C ATOM 2202 O ARG A 282 68.884 34.498 0.367 1.00 118.62 O ATOM 2203 CB ARG A 282 71.590 33.929 −0.431 1.00 127.68 C ATOM 2204 CG ARG A 282 72.734 32.955 −0.182 1.00 143.60 C ATOM 2205 CD ARG A 282 74.036 33.669 0.180 1.00 140.72 C ATOM 2206 NE ARG A 282 74.082 35.072 −0.259 1.00 148.97 N ATOM 2207 CZ ARG A 282 74.155 35.496 −1.525 1.00 145.20 C ATOM 2208 NH1 ARG A 282 74.171 34.638 −2.541 1.00 145.19 N ATOM 2209 NH2 ARG A 282 74.191 36.797 −1.779 1.00 135.62 N ATOM 2210 N ASN A 283 68.366 34.526 −1.825 1.00 113.36 N ATOM 2211 CA ASN A 283 67.107 35.243 −1.628 1.00 106.59 C ATOM 2212 C ASN A 283 65.901 34.310 −1.804 1.00 110.16 C ATOM 2213 O ASN A 283 64.756 34.752 −1.859 1.00 108.80 O ATOM 2214 CB ASN A 283 67.024 36.450 −2.578 1.00 98.10 C ATOM 2215 CG ASN A 283 66.939 36.051 −4.052 1.00 103.94 C ATOM 2216 OD1 ASN A 283 66.666 34.895 −4.403 1.00 100.67 O ATOM 2217 ND2 ASN A 283 67.158 37.024 −4.925 1.00 100.07 N ATOM 2218 N LEU A 284 66.184 33.014 −1.871 1.00 112.50 N ATOM 2219 CA LEU A 284 65.244 31.997 −2.347 1.00 107.73 C ATOM 2220 C LEU A 284 63.928 31.796 −1.561 1.00 98.27 C ATOM 2221 O LEU A 284 62.955 31.268 −2.100 1.00 93.09 O ATOM 2222 CB LEU A 284 65.984 30.668 −2.471 1.00 114.87 C ATOM 2223 CG LEU A 284 65.512 29.777 −3.612 1.00 126.71 C ATOM 2224 CD1 LEU A 284 65.723 30.473 −4.950 1.00 128.74 C ATOM 2225 CD2 LEU A 284 66.249 28.452 −3.564 1.00 126.73 C ATOM 2226 N SER A 285 63.907 32.181 −0.294 1.00 87.21 N ATOM 2227 CA SER A 285 62.689 32.099 0.497 1.00 96.03 C ATOM 2228 C SER A 285 62.064 33.487 0.712 1.00 107.07 C ATOM 2229 O SER A 285 61.034 33.610 1.385 1.00 103.89 O ATOM 2230 CB SER A 285 62.999 31.471 1.846 1.00 98.40 C ATOM 2231 OG SER A 285 63.978 32.240 2.527 1.00 91.85 O ATOM 2232 N ASP A 286 62.713 34.521 0.165 1.00 109.54 N ATOM 2233 CA ASP A 286 62.175 35.880 0.147 1.00 105.53 C ATOM 2234 C ASP A 286 60.906 35.878 −0.673 1.00 107.48 C ATOM 2235 O ASP A 286 60.879 35.336 −1.803 1.00 91.71 O ATOM 2236 CB ASP A 286 63.147 36.874 −0.497 1.00 111.23 C ATOM 2237 CG ASP A 286 64.406 37.087 0.317 1.00 120.12 C ATOM 2238 OD1 ASP A 286 64.413 36.758 1.522 1.00 123.58 O ATOM 2239 OD2 ASP A 286 65.391 37.603 −0.252 1.00 127.64 O ATOM 2240 N ILE A 287 59.869 36.495 −0.099 1.00 96.69 N ATOM 2241 CA ILE A 287 58.562 36.635 −0.743 1.00 84.00 C ATOM 2242 C ILE A 287 58.667 37.193 −2.161 1.00 76.52 C ATOM 2243 O ILE A 287 57.899 36.822 −3.035 1.00 76.12 O ATOM 2244 CB ILE A 287 57.641 37.497 0.117 1.00 81.83 C ATOM 2245 CG1 ILE A 287 56.180 37.154 −0.165 1.00 82.11 C ATOM 2246 CG2 ILE A 287 57.961 38.973 −0.053 1.00 82.30 C ATOM 2247 CD1 ILE A 287 55.287 37.435 1.028 1.00 86.82 C ATOM 2248 N GLY A 288 59.668 38.039 −2.385 1.00 76.34 N ATOM 2249 CA GLY A 288 59.952 38.576 −3.702 1.00 77.28 C ATOM 2250 C GLY A 288 59.988 37.561 −4.823 1.00 76.68 C ATOM 2251 O GLY A 288 60.073 37.923 −5.988 1.00 86.71 O ATOM 2252 N THR A 289 59.935 36.286 −4.486 1.00 83.61 N ATOM 2253 CA THR A 289 60.097 35.260 −5.508 1.00 95.38 C ATOM 2254 C THR A 289 58.743 34.812 −6.010 1.00 94.17 C ATOM 2255 O THR A 289 58.624 34.225 −7.094 1.00 95.27 O ATOM 2256 CB THR A 289 60.900 34.052 −4.990 1.00 90.75 C ATOM 2257 OG1 THR A 289 60.328 33.597 −3.764 1.00 91.90 O ATOM 2258 CG2 THR A 289 62.333 34.457 −4.730 1.00 97.09 C ATOM 2259 N ILE A 290 57.719 35.106 −5.221 1.00 88.58 N ATOM 2260 CA ILE A 290 56.382 34.677 −5.584 1.00 86.90 C ATOM 2261 C ILE A 290 55.445 35.814 −5.978 1.00 82.87 C ATOM 2262 O ILE A 290 54.245 35.596 −6.167 1.00 82.60 O ATOM 2263 CB ILE A 290 55.752 33.804 −4.491 1.00 85.43 C ATOM 2264 CG1 ILE A 290 55.751 34.514 −3.141 1.00 80.60 C ATOM 2265 CG2 ILE A 290 56.493 32.483 −4.408 1.00 95.57 C ATOM 2266 CD1 ILE A 290 54.639 34.034 −2.232 1.00 80.76 C ATOM 2267 N MET A 291 55.989 37.020 −6.118 1.00 76.16 N ATOM 2268 CA MET A 291 55.153 38.162 −6.471 1.00 75.58 C ATOM 2269 C MET A 291 55.784 39.208 −7.368 1.00 76.19 C ATOM 2270 O MET A 291 56.904 39.665 −7.096 1.00 77.68 O ATOM 2271 CB MET A 291 54.629 38.847 −5.211 1.00 71.10 C ATOM 2272 CG MET A 291 55.703 39.372 −4.294 1.00 67.78 C ATOM 2273 SD MET A 291 55.023 40.225 −2.851 1.00 70.94 S ATOM 2274 CE MET A 291 53.723 39.139 −2.266 1.00 63.88 C ATOM 2275 N ARG A 292 55.046 39.599 −8.416 1.00 76.28 N ATOM 2276 CA ARG A 292 55.369 40.806 −9.179 1.00 75.00 C ATOM 2277 C ARG A 292 55.082 41.997 −8.267 1.00 71.17 C ATOM 2278 O ARG A 292 54.171 41.951 −7.450 1.00 76.45 O ATOM 2279 CB ARG A 292 54.531 40.909 −10.443 1.00 79.51 C ATOM 2280 CG ARG A 292 55.024 40.083 −11.612 1.00 92.46 C ATOM 2281 CD ARG A 292 54.142 40.274 −12.841 1.00 92.16 C ATOM 2282 NE ARG A 292 52.947 39.424 −12.829 1.00 94.54 N ATOM 2283 CZ ARG A 292 51.688 39.862 −12.959 1.00 103.49 C ATOM 2284 NH1 ARG A 292 51.435 41.161 −13.113 1.00 99.39 N ATOM 2285 NH2 ARG A 292 50.668 38.996 −12.943 1.00 96.59 N ATOM 2286 N VAL A 293 55.884 43.039 −8.393 1.00 67.83 N ATOM 2287 CA VAL A 293 55.706 44.278 −7.658 1.00 70.55 C ATOM 2288 C VAL A 293 55.818 45.463 −8.633 1.00 76.23 C ATOM 2289 O VAL A 293 56.736 45.511 −9.450 1.00 78.92 O ATOM 2290 CB VAL A 293 56.765 44.375 −6.548 1.00 68.24 C ATOM 2291 CG1 VAL A 293 56.857 45.783 −5.971 1.00 72.25 C ATOM 2292 CG2 VAL A 293 56.440 43.380 −5.457 1.00 70.38 C ATOM 2293 N VAL A 294 54.877 46.401 −8.597 1.00 77.94 N ATOM 2294 CA VAL A 294 55.068 47.628 −9.395 1.00 77.96 C ATOM 2295 C VAL A 294 54.848 48.848 −8.521 1.00 81.79 C ATOM 2296 O VAL A 294 54.087 48.798 −7.549 1.00 84.11 O ATOM 2297 CB VAL A 294 54.199 47.710 −10.687 1.00 69.45 C ATOM 2298 CG1 VAL A 294 53.537 46.389 −11.027 1.00 63.21 C ATOM 2299 CG2 VAL A 294 53.121 48.765 −10.555 1.00 82.95 C ATOM 2300 N GLU A 295 55.533 49.937 −8.858 1.00 89.24 N ATOM 2301 CA GLU A 295 55.241 51.229 −8.250 1.00 81.68 C ATOM 2302 C GLU A 295 54.122 51.898 −9.033 1.00 76.96 C ATOM 2303 O GLU A 295 54.233 52.096 −10.243 1.00 73.82 O ATOM 2304 CB GLU A 295 56.473 52.105 −8.243 1.00 79.52 C ATOM 2305 CG GLU A 295 56.359 53.300 −7.321 1.00 79.68 C ATOM 2306 CD GLU A 295 57.707 53.928 −7.015 1.00 84.18 C ATOM 2307 OE1 GLU A 295 58.674 53.744 −7.793 1.00 86.03 O ATOM 2308 OE2 GLU A 295 57.805 54.612 −5.985 1.00 89.42 O ATOM 2309 N LEU A 296 53.028 52.205 −8.343 1.00 77.19 N ATOM 2310 CA LEU A 296 51.929 52.946 −8.945 1.00 71.24 C ATOM 2311 C LEU A 296 52.228 54.436 −8.946 1.00 77.84 C ATOM 2312 O LEU A 296 52.836 54.983 −7.998 1.00 75.09 O ATOM 2313 CB LEU A 296 50.636 52.696 −8.206 1.00 59.82 C ATOM 2314 CG LEU A 296 50.244 51.225 −8.231 1.00 65.06 C ATOM 2315 CD1 LEU A 296 49.269 50.898 −7.116 1.00 65.94 C ATOM 2316 CD2 LEU A 296 49.687 50.754 −9.569 1.00 61.75 C ATOM 2317 N SER A 297 51.787 55.072 −10.031 1.00 80.32 N ATOM 2318 CA SER A 297 51.848 56.509 −10.197 1.00 73.23 C ATOM 2319 C SER A 297 51.019 57.169 −9.093 1.00 75.78 C ATOM 2320 O SER A 297 49.864 56.785 −8.837 1.00 76.09 O ATOM 2321 CB SER A 297 51.304 56.892 −11.573 1.00 76.30 C ATOM 2322 OG SER A 297 52.000 56.242 −12.635 1.00 82.54 O ATOM 2323 N PRO A 298 51.615 58.147 −8.410 1.00 68.91 N ATOM 2324 CA PRO A 298 50.902 58.942 −7.422 1.00 72.69 C ATOM 2325 C PRO A 298 49.941 59.948 −8.087 1.00 78.50 C ATOM 2326 O PRO A 298 50.028 60.193 −9.303 1.00 82.69 O ATOM 2327 CB PRO A 298 52.028 59.722 −6.763 1.00 78.86 C ATOM 2328 CG PRO A 298 53.003 59.946 −7.883 1.00 74.51 C ATOM 2329 CD PRO A 298 52.948 58.693 −8.720 1.00 67.08 C ATOM 2330 N LEU A 299 49.048 60.540 −7.301 1.00 78.63 N ATOM 2331 CA LEU A 299 48.249 61.667 −7.781 1.00 78.34 C ATOM 2332 C LEU A 299 49.013 62.975 −7.598 1.00 83.46 C ATOM 2333 O LEU A 299 49.596 63.191 −6.526 1.00 95.24 O ATOM 2334 CB LEU A 299 46.946 61.738 −7.004 1.00 75.43 C ATOM 2335 CG LEU A 299 45.670 61.189 −7.620 1.00 74.16 C ATOM 2336 CD1 LEU A 299 44.551 61.474 −6.628 1.00 72.23 C ATOM 2337 CD2 LEU A 299 45.397 61.866 −8.955 1.00 71.49 C ATOM 2338 N LYS A 300 49.015 63.849 −8.611 1.00 84.11 N ATOM 2339 CA LYS A 300 49.678 65.170 −8.476 1.00 91.37 C ATOM 2340 C LYS A 300 49.272 65.950 −7.219 1.00 99.03 C ATOM 2341 O LYS A 300 50.114 66.580 −6.563 1.00 97.10 O ATOM 2342 CB LYS A 300 49.490 66.035 −9.718 1.00 90.47 C ATOM 2343 CG LYS A 300 50.777 66.246 −10.505 1.00 106.46 C ATOM 2344 CD LYS A 300 51.471 67.566 −10.181 1.00 101.75 C ATOM 2345 CE LYS A 300 52.738 67.729 −11.004 1.00 95.35 C ATOM 2346 NZ LYS A 300 53.031 69.172 −11.216 1.00 102.17 N ATOM 2347 N GLY A 301 47.991 65.884 −6.870 1.00 100.53 N ATOM 2348 CA GLY A 301 47.514 66.522 −5.649 1.00 119.44 C ATOM 2349 C GLY A 301 47.510 65.611 −4.441 1.00 125.52 C ATOM 2350 O GLY A 301 46.543 65.612 −3.675 1.00 135.41 O ATOM 2351 N SER A 302 48.588 64.840 −4.272 1.00 123.02 N ATOM 2352 CA SER A 302 48.723 63.885 −3.164 1.00 121.56 C ATOM 2353 C SER A 302 48.752 64.603 −1.819 1.00 131.11 C ATOM 2354 O SER A 302 49.364 65.669 −1.703 1.00 140.60 O ATOM 2355 CB SER A 302 50.010 63.072 −3.316 1.00 113.11 C ATOM 2356 OG SER A 302 51.155 63.862 −3.006 1.00 108.08 O ATOM 2357 N VAL A 303 48.100 64.015 −0.811 1.00 137.77 N ATOM 2358 CA VAL A 303 48.179 64.503 0.579 1.00 144.45 C ATOM 2359 C VAL A 303 49.659 64.729 0.937 1.00 152.42 C ATOM 2360 O VAL A 303 49.984 65.595 1.754 1.00 163.65 O ATOM 2361 CB VAL A 303 47.479 63.541 1.588 1.00 141.04 C ATOM 2362 CG1 VAL A 303 47.569 64.066 3.022 1.00 132.21 C ATOM 2363 CG2 VAL A 303 46.020 63.299 1.199 1.00 127.02 C ATOM 2364 N SER A 304 50.534 63.947 0.294 1.00 155.40 N ATOM 2365 CA SER A 304 51.995 64.109 0.324 1.00 155.10 C ATOM 2366 C SER A 304 52.584 63.995 1.737 1.00 170.59 C ATOM 2367 O SER A 304 53.143 64.964 2.268 1.00 183.96 O ATOM 2368 CB SER A 304 52.398 65.426 −0.353 1.00 148.14 C ATOM 2369 OG SER A 304 53.627 65.295 −1.036 1.00 148.61 O ATOM 2370 N TRP A 305 52.461 62.804 2.330 1.00 168.67 N ATOM 2371 CA TRP A 305 52.866 62.563 3.721 1.00 168.54 C ATOM 2372 C TRP A 305 54.329 62.835 3.903 1.00 170.55 C ATOM 2373 O TRP A 305 55.113 62.662 2.965 1.00 172.15 O ATOM 2374 CB TRP A 305 52.538 61.131 4.146 1.00 178.71 C ATOM 2375 CG TRP A 305 51.909 61.038 5.522 1.00 191.21 C ATOM 2376 CD1 TRP A 305 50.562 60.825 5.827 1.00 192.74 C ATOM 2377 CD2 TRP A 305 52.579 61.166 6.836 1.00 192.86 C ATOM 2378 NE1 TRP A 305 50.362 60.807 7.186 1.00 196.91 N ATOM 2379 CE2 TRP A 305 51.527 61.006 7.850 1.00 198.98 C ATOM 2380 CE3 TRP A 305 53.893 61.381 7.256 1.00 179.82 C ATOM 2381 CZ2 TRP A 305 51.803 61.067 9.214 1.00 193.12 C ATOM 2382 CZ3 TRP A 305 54.157 61.444 8.632 1.00 171.12 C ATOM 2383 CH2 TRP A 305 53.137 61.289 9.585 1.00 181.41 C ATOM 2384 N THR A 306 54.700 63.257 5.116 1.00 164.44 N ATOM 2385 CA THR A 306 56.075 63.662 5.482 1.00 153.53 C ATOM 2386 C THR A 306 56.593 64.851 4.655 1.00 152.44 C ATOM 2387 O THR A 306 57.778 64.922 4.314 1.00 146.98 O ATOM 2388 CB THR A 306 57.089 62.466 5.571 1.00 151.56 C ATOM 2389 OG1 THR A 306 58.413 62.966 5.786 1.00 160.90 O ATOM 2390 CG2 THR A 306 57.108 61.579 4.318 1.00 142.50 C ATOM 2391 N GLY A 307 55.684 65.788 4.365 1.00 149.27 N ATOM 2392 CA GLY A 307 55.970 66.977 3.551 1.00 153.87 C ATOM 2393 C GLY A 307 56.757 66.657 2.292 1.00 158.97 C ATOM 2394 O GLY A 307 57.705 67.364 1.938 1.00 160.20 O ATOM 2395 N LYS A 308 56.350 65.590 1.611 1.00 160.14 N ATOM 2396 CA LYS A 308 57.165 64.959 0.577 1.00 159.00 C ATOM 2397 C LYS A 308 56.270 64.045 −0.284 1.00 152.38 C ATOM 2398 O LYS A 308 55.399 63.354 0.258 1.00 141.53 O ATOM 2399 CB LYS A 308 58.298 64.167 1.259 1.00 142.65 C ATOM 2400 CG LYS A 308 59.445 63.705 0.375 1.00 134.77 C ATOM 2401 CD LYS A 308 59.258 62.275 −0.119 1.00 126.20 C ATOM 2402 CE LYS A 308 58.904 61.309 1.003 1.00 123.04 C ATOM 2403 NZ LYS A 308 59.777 61.461 2.200 1.00 114.87 N ATOM 2404 N PRO A 309 56.451 64.071 −1.628 1.00 147.37 N ATOM 2405 CA PRO A 309 55.661 63.178 −2.499 1.00 141.37 C ATOM 2406 C PRO A 309 55.954 61.687 −2.255 1.00 141.82 C ATOM 2407 O PRO A 309 57.120 61.278 −2.201 1.00 144.06 O ATOM 2408 CB PRO A 309 56.070 63.607 −3.917 1.00 125.34 C ATOM 2409 CG PRO A 309 56.595 64.998 −3.759 1.00 135.55 C ATOM 2410 CD PRO A 309 57.262 65.023 −2.413 1.00 138.97 C ATOM 2411 N VAL A 310 54.896 60.896 −2.085 1.00 130.69 N ATOM 2412 CA VAL A 310 55.022 59.464 −1.791 1.00 131.06 C ATOM 2413 C VAL A 310 54.166 58.667 −2.782 1.00 126.43 C ATOM 2414 O VAL A 310 53.081 59.120 −3.165 1.00 124.65 O ATOM 2415 CB VAL A 310 54.651 59.156 −0.304 1.00 138.87 C ATOM 2416 CG1 VAL A 310 54.094 57.744 −0.118 1.00 132.34 C ATOM 2417 CG2 VAL A 310 55.849 59.388 0.619 1.00 132.03 C ATOM 2418 N SER A 311 54.658 57.499 −3.208 1.00 111.56 N ATOM 2419 CA SER A 311 53.870 56.613 −4.079 1.00 104.58 C ATOM 2420 C SER A 311 53.520 55.278 −3.413 1.00 88.55 C ATOM 2421 O SER A 311 53.717 55.108 −2.210 1.00 83.20 O ATOM 2422 CB SER A 311 54.541 56.396 −5.435 1.00 106.30 C ATOM 2423 OG SER A 311 55.504 55.373 −5.336 1.00 107.88 O ATOM 2424 N TYR A 312 52.974 54.354 −4.201 1.00 79.26 N ATOM 2425 CA TYR A 312 52.304 53.165 −3.668 1.00 79.08 C ATOM 2426 C TYR A 312 52.586 51.981 −4.563 1.00 76.54 C ATOM 2427 O TYR A 312 53.082 52.150 −5.685 1.00 68.58 O ATOM 2428 CB TYR A 312 50.781 53.390 −3.566 1.00 80.09 C ATOM 2429 CG TYR A 312 50.463 54.753 −3.056 1.00 85.43 C ATOM 2430 CD1 TYR A 312 50.473 55.018 −1.685 1.00 94.54 C ATOM 2431 CD2 TYR A 312 50.221 55.809 −3.943 1.00 93.43 C ATOM 2432 CE1 TYR A 312 50.224 56.294 −1.206 1.00 102.27 C ATOM 2433 CE2 TYR A 312 49.979 57.090 −3.475 1.00 93.42 C ATOM 2434 CZ TYR A 312 49.981 57.321 −2.110 1.00 100.39 C ATOM 2435 OH TYR A 312 49.736 58.583 −1.639 1.00 119.09 O ATOM 2436 N TYR A 313 52.225 50.792 −4.078 1.00 72.47 N ATOM 2437 CA TYR A 313 52.769 49.562 −4.616 1.00 62.45 C ATOM 2438 C TYR A 313 51.744 48.470 −4.791 1.00 65.28 C ATOM 2439 O TYR A 313 50.982 48.129 −3.875 1.00 73.20 O ATOM 2440 CB TYR A 313 53.911 49.091 −3.737 1.00 58.83 C ATOM 2441 CG TYR A 313 55.006 50.127 −3.569 1.00 64.33 C ATOM 2442 CD1 TYR A 313 55.982 50.292 −4.537 1.00 67.83 C ATOM 2443 CD2 TYR A 313 55.057 50.939 −2.441 1.00 64.55 C ATOM 2444 CE1 TYR A 313 56.980 51.242 −4.389 1.00 72.85 C ATOM 2445 CE2 TYR A 313 56.049 51.882 −2.282 1.00 67.15 C ATOM 2446 CZ TYR A 313 57.005 52.034 −3.259 1.00 72.31 C ATOM 2447 OH TYR A 313 58.001 52.976 −3.108 1.00 76.67 O ATOM 2448 N LEU A 314 51.725 47.931 −5.998 1.00 61.90 N ATOM 2449 CA LEU A 314 50.870 46.811 −6.319 1.00 67.08 C ATOM 2450 C LEU A 314 51.709 45.529 −6.383 1.00 72.17 C ATOM 2451 O LEU A 314 52.651 45.419 −7.190 1.00 72.07 O ATOM 2452 CB LEU A 314 50.156 47.071 −7.653 1.00 59.23 C ATOM 2453 CG LEU A 314 49.479 45.876 −8.337 1.00 62.96 C ATOM 2454 CD1 LEU A 314 48.302 45.278 −7.553 1.00 55.90 C ATOM 2455 CD2 LEU A 314 49.091 46.254 −9.765 1.00 56.83 C ATOM 2456 N HIS A 315 51.371 44.574 −5.523 1.00 71.77 N ATOM 2457 CA HIS A 315 52.008 43.266 −5.553 1.00 69.03 C ATOM 2458 C HIS A 315 51.008 42.267 −6.017 1.00 67.34 C ATOM 2459 O HIS A 315 49.905 42.171 −5.481 1.00 71.85 O ATOM 2460 CB HIS A 315 52.532 42.819 −4.184 1.00 69.91 C ATOM 2461 CG HIS A 315 53.069 43.929 −3.295 1.00 70.86 C ATOM 2462 ND1 HIS A 315 52.272 44.829 −2.695 1.00 75.74 N ATOM 2463 CD2 HIS A 315 54.356 44.188 −2.840 1.00 72.03 C ATOM 2464 CE1 HIS A 315 53.014 45.649 −1.925 1.00 75.47 C ATOM 2465 NE2 HIS A 315 54.287 45.260 −2.017 1.00 77.00 N ATOM 2466 N THR A 316 51.388 41.497 −7.017 1.00 70.99 N ATOM 2467 CA THR A 316 50.546 40.418 −7.506 1.00 75.93 C ATOM 2468 C THR A 316 51.250 39.081 −7.238 1.00 80.12 C ATOM 2469 O THR A 316 52.397 38.870 −7.669 1.00 72.92 O ATOM 2470 CB THR A 316 50.268 40.594 −9.016 1.00 73.68 C ATOM 2471 OG1 THR A 316 49.686 41.883 −9.232 1.00 78.35 O ATOM 2472 CG2 THR A 316 49.318 39.523 −9.537 1.00 66.60 C ATOM 2473 N ILE A 317 50.568 38.197 −6.509 1.00 79.40 N ATOM 2474 CA ILE A 317 51.025 36.822 −6.336 1.00 78.30 C ATOM 2475 C ILE A 317 51.183 36.165 −7.712 1.00 86.07 C ATOM 2476 O ILE A 317 50.194 35.883 −8.413 1.00 83.61 O ATOM 2477 CB ILE A 317 50.052 35.993 −5.461 1.00 72.56 C ATOM 2478 CG1 ILE A 317 50.022 36.496 −4.018 1.00 69.65 C ATOM 2479 CG2 ILE A 317 50.440 34.525 −5.448 1.00 80.76 C ATOM 2480 CD1 ILE A 317 51.368 36.864 −3.426 1.00 68.78 C ATOM 2481 N ASP A 318 52.439 35.948 −8.093 1.00 89.92 N ATOM 2482 CA ASP A 318 52.789 35.252 −9.333 1.00 92.89 C ATOM 2483 C ASP A 318 53.905 34.214 −9.089 1.00 94.09 C ATOM 2484 O ASP A 318 55.102 34.566 −9.054 1.00 88.00 O ATOM 2485 CB ASP A 318 53.198 36.276 −10.394 1.00 89.90 C ATOM 2486 CG ASP A 318 53.631 35.640 −11.691 1.00 93.99 C ATOM 2487 OD1 ASP A 318 53.229 34.482 −11.966 1.00 90.26 O ATOM 2488 OD2 ASP A 318 54.370 36.323 −12.438 1.00 95.88 O ATOM 2489 N ARG A 319 53.508 32.947 −8.906 1.00 84.46 N ATOM 2490 CA ARG A 319 54.480 31.869 −8.612 1.00 89.38 C ATOM 2491 C ARG A 319 55.371 31.455 −9.772 1.00 88.53 C ATOM 2492 O ARG A 319 56.532 31.128 −9.566 1.00 87.53 O ATOM 2493 CB ARG A 319 53.809 30.637 −8.025 1.00 83.51 C ATOM 2494 CG ARG A 319 53.975 30.566 −6.529 1.00 82.51 C ATOM 2495 CD ARG A 319 52.659 30.225 −5.880 1.00 78.57 C ATOM 2496 NE ARG A 319 52.671 30.604 −4.475 1.00 78.70 N ATOM 2497 CZ ARG A 319 51.580 30.929 −3.791 1.00 85.46 C ATOM 2498 NH1 ARG A 319 50.398 30.930 −4.394 1.00 86.59 N ATOM 2499 NH2 ARG A 319 51.663 31.256 −2.509 1.00 84.76 N ATOM 2500 N THR A 320 54.831 31.473 −10.983 1.00 82.07 N ATOM 2501 CA THR A 320 55.628 31.188 −12.156 1.00 83.33 C ATOM 2502 C THR A 320 57.010 31.867 −12.128 1.00 90.69 C ATOM 2503 O THR A 320 57.951 31.359 −12.734 1.00 95.36 O ATOM 2504 CB THR A 320 54.894 31.564 −13.464 1.00 85.36 C ATOM 2505 OG1 THR A 320 55.018 32.978 −13.715 1.00 73.28 O ATOM 2506 CG2 THR A 320 53.408 31.096 −13.438 1.00 73.13 C ATOM 2507 N ILE A 321 57.128 33.010 −11.444 1.00 95.96 N ATOM 2508 CA ILE A 321 58.433 33.672 −11.259 1.00 94.64 C ATOM 2509 C ILE A 321 59.420 32.670 −10.662 1.00 93.70 C ATOM 2510 O ILE A 321 60.534 32.522 −11.160 1.00 96.07 O ATOM 2511 CB ILE A 321 58.363 34.911 −10.326 1.00 93.79 C ATOM 2512 CG1 ILE A 321 57.452 36.004 −10.898 1.00 99.78 C ATOM 2513 CG2 ILE A 321 59.753 35.483 −10.064 1.00 80.61 C ATOM 2514 CD1 ILE A 321 57.167 37.129 −9.913 1.00 96.93 C ATOM 2515 N LEU A 322 58.993 31.991 −9.596 1.00 87.70 N ATOM 2516 CA LEU A 322 59.761 30.913 −8.965 1.00 85.26 C ATOM 2517 C LEU A 322 59.982 29.750 −9.937 1.00 92.53 C ATOM 2518 O LEU A 322 61.122 29.335 −10.178 1.00 89.44 O ATOM 2519 CB LEU A 322 59.031 30.412 −7.713 1.00 74.26 C ATOM 2520 CG LEU A 322 59.804 29.614 −6.662 1.00 74.13 C ATOM 2521 CD1 LEU A 322 61.033 30.355 −6.144 1.00 72.69 C ATOM 2522 CD2 LEU A 322 58.903 29.212 −5.506 1.00 67.18 C ATOM 2523 N GLU A 323 58.881 29.245 −10.498 1.00 94.51 N ATOM 2524 CA GLU A 323 58.914 28.176 −11.495 1.00 92.52 C ATOM 2525 C GLU A 323 59.990 28.436 −12.551 1.00 93.78 C ATOM 2526 O GLU A 323 60.826 27.579 −12.798 1.00 101.05 O ATOM 2527 CB GLU A 323 57.525 27.954 −12.109 1.00 88.46 C ATOM 2528 CG GLU A 323 56.479 27.595 −11.056 1.00 100.05 C ATOM 2529 CD GLU A 323 55.053 27.480 −11.581 1.00 110.58 C ATOM 2530 OE1 GLU A 323 54.775 27.988 −12.691 1.00 112.02 O ATOM 2531 OE2 GLU A 323 54.203 26.879 −10.872 1.00 107.65 O ATOM 2532 N ASN A 324 60.006 29.635 −13.121 1.00 97.99 N ATOM 2533 CA ASN A 324 61.020 30.001 −14.106 1.00 103.97 C ATOM 2534 C ASN A 324 62.461 29.839 −13.620 1.00 107.46 C ATOM 2535 O ASN A 324 63.335 29.504 −14.414 1.00 118.90 O ATOM 2536 CB ASN A 324 60.795 31.420 −14.629 1.00 109.87 C ATOM 2537 CG ASN A 324 59.498 31.559 −15.408 1.00 112.74 C ATOM 2538 OD1 ASN A 324 58.785 30.578 −15.653 1.00 104.32 O ATOM 2539 ND2 ASN A 324 59.180 32.791 −15.793 1.00 119.62 N ATOM 2540 N TYR A 325 62.707 30.065 −12.331 1.00 97.93 N ATOM 2541 CA TYR A 325 64.052 29.894 −11.760 1.00 104.99 C ATOM 2542 C TYR A 325 64.432 28.417 −11.595 1.00 110.62 C ATOM 2543 O TYR A 325 65.600 28.088 −11.391 1.00 105.64 O ATOM 2544 CB TYR A 325 64.150 30.622 −10.424 1.00 106.27 C ATOM 2545 CG TYR A 325 65.507 30.603 −9.738 1.00 116.07 C ATOM 2546 CD1 TYR A 325 66.561 31.409 −10.187 1.00 119.17 C ATOM 2547 CD2 TYR A 325 65.722 29.818 −8.603 1.00 119.90 C ATOM 2548 CE1 TYR A 325 67.793 31.415 −9.537 1.00 118.89 C ATOM 2549 CE2 TYR A 325 66.950 29.819 −7.949 1.00 123.43 C ATOM 2550 CZ TYR A 325 67.981 30.618 −8.415 1.00 124.19 C ATOM 2551 OH TYR A 325 69.193 30.617 −7.755 1.00 121.24 O ATOM 2552 N PHE A 326 63.433 27.540 −11.676 1.00 112.98 N ATOM 2553 CA PHE A 326 63.659 26.102 −11.651 1.00 110.62 C ATOM 2554 C PHE A 326 63.660 25.519 −13.061 1.00 116.54 C ATOM 2555 O PHE A 326 64.229 24.457 −13.295 1.00 132.07 O ATOM 2556 CB PHE A 326 62.637 25.398 −10.757 1.00 98.67 C ATOM 2557 CG PHE A 326 62.946 25.501 −9.284 1.00 111.70 C ATOM 2558 CD1 PHE A 326 62.334 26.470 −8.489 1.00 123.02 C ATOM 2559 CD2 PHE A 326 63.852 24.633 −8.681 1.00 110.37 C ATOM 2560 CE1 PHE A 326 62.614 26.564 −7.124 1.00 110.31 C ATOM 2561 CE2 PHE A 326 64.135 24.727 −7.320 1.00 107.89 C ATOM 2562 CZ PHE A 326 63.517 25.693 −6.540 1.00 99.82 C ATOM 2563 N SER A 327 63.025 26.214 −13.998 1.00 119.38 N ATOM 2564 CA SER A 327 63.168 25.888 −15.412 1.00 122.32 C ATOM 2565 C SER A 327 64.544 26.329 −15.885 1.00 125.23 C ATOM 2566 O SER A 327 65.127 25.709 −16.776 1.00 130.69 O ATOM 2567 CB SER A 327 62.102 26.591 −16.253 1.00 120.62 C ATOM 2568 OG SER A 327 60.809 26.122 −15.934 1.00 124.28 O ATOM 2569 N SER A 328 65.060 27.396 −15.275 1.00 117.67 N ATOM 2570 CA SER A 328 66.321 27.985 −15.708 1.00 122.09 C ATOM 2571 C SER A 328 67.516 27.234 −15.136 1.00 129.01 C ATOM 2572 O SER A 328 68.641 27.737 −15.148 1.00 133.36 O ATOM 2573 CB SER A 328 66.394 29.468 −15.341 1.00 113.67 C ATOM 2574 OG SER A 328 66.566 29.629 −13.945 1.00 120.73 O ATOM 2575 N LEU A 329 67.275 26.032 −14.628 1.00 133.64 N ATOM 2576 CA LEU A 329 68.369 25.184 −14.177 1.00 129.59 C ATOM 2577 C LEU A 329 68.321 23.828 −14.903 1.00 128.70 C ATOM 2578 O LEU A 329 68.065 22.776 −14.311 1.00 125.46 O ATOM 2579 CB LEU A 329 68.413 25.104 −12.637 1.00 122.10 C ATOM 2580 CG LEU A 329 68.586 26.456 −11.896 1.00 115.92 C ATOM 2581 CD1 LEU A 329 68.375 26.351 −10.389 1.00 109.03 C ATOM 2582 CD2 LEU A 329 69.929 27.120 −12.180 1.00 114.03 C ATOM 2583 N LYS A 330 68.515 23.915 −16.221 1.00 134.82 N ATOM 2584 CA LYS A 330 68.783 22.779 −17.108 1.00 131.88 C ATOM 2585 C LYS A 330 70.109 23.024 −17.827 1.00 136.09 C ATOM 2586 O LYS A 330 70.734 24.079 −17.663 1.00 126.76 O ATOM 2587 CB LYS A 330 67.658 22.579 −18.137 1.00 121.64 C ATOM 2588 CG LYS A 330 66.649 21.509 −17.754 1.00 124.92 C ATOM 2589 CD LYS A 330 65.809 21.947 −16.563 1.00 128.51 C ATOM 2590 CE LYS A 330 65.620 20.811 −15.574 1.00 120.92 C ATOM 2591 NZ LYS A 330 65.346 21.322 −14.205 1.00 108.06 N TER 2592 LYS A 330 HETATM 2593 C2 0QK A 501 43.267 45.305 13.198 1.00 83.36 C HETATM 2594 C4 0QK A 501 44.663 47.218 13.113 1.00 83.08 C HETATM 2595 C5 0QK A 501 45.752 46.461 13.245 1.00 81.52 C HETATM 2596 C6 0QK A 501 45.621 45.130 13.364 1.00 85.38 C HETATM 2597 CBI 0QK A 501 46.059 53.920 −1.025 1.00 71.41 C HETATM 2598 CBH 0QK A 501 46.534 52.809 −0.099 1.00 69.19 C HETATM 2599 CBJ 0QK A 501 47.867 53.233 0.529 1.00 74.95 C HETATM 2600 CBK 0QK A 501 46.726 51.592 −0.999 1.00 65.05 C HETATM 2601 CBE 0QK A 501 45.595 52.578 0.943 1.00 69.40 C HETATM 2602 CBF 0QK A 501 45.385 51.301 1.487 1.00 62.58 C HETATM 2603 CBG 0QK A 501 44.446 51.137 2.514 1.00 64.53 C HETATM 2604 CBD 0QK A 501 44.848 53.660 1.463 1.00 65.92 C HETATM 2605 CBC 0QK A 501 43.913 53.483 2.490 1.00 62.12 C HETATM 2606 CBB 0QK A 501 43.700 52.212 3.039 1.00 62.70 C HETATM 2607 NAZ 0QK A 501 42.784 51.978 4.018 1.00 58.88 N HETATM 2608 CAY 0QK A 501 42.641 52.830 5.059 1.00 62.60 C HETATM 2609 OBA 0QK A 501 43.366 53.838 5.157 1.00 60.66 O HETATM 2610 NAX 0QK A 501 41.662 52.535 5.982 1.00 61.84 N HETATM 2611 CAW 0QK A 501 41.509 53.290 7.245 1.00 57.19 C HETATM 2612 CAV 0QK A 501 43.004 53.502 7.636 1.00 72.05 C HETATM 2613 CAT 0QK A 501 43.356 53.210 9.083 1.00 82.20 C HETATM 2614 NAS 0QK A 501 44.380 52.162 9.356 1.00 79.95 N HETATM 2615 CAU 0QK A 501 45.691 52.155 8.674 1.00 80.80 C HETATM 2616 CBM 0QK A 501 46.400 50.805 8.939 1.00 78.40 C HETATM 2617 CBL 0QK A 501 46.645 53.288 9.116 1.00 66.71 C HETATM 2618 CAR 0QK A 501 44.642 52.265 10.805 1.00 82.82 C HETATM 2619 CAN 0QK A 501 43.660 51.404 11.595 1.00 86.49 C HETATM 2620 OAO 0QK A 501 44.209 50.082 11.555 1.00 87.99 O HETATM 2621 CAM 0QK A 501 43.665 51.850 13.042 1.00 83.94 C HETATM 2622 OAQ 0QK A 501 42.321 51.998 13.460 1.00 80.10 O HETATM 2623 CAL 0QK A 501 44.331 50.699 13.787 1.00 84.69 C HETATM 2624 OAP 0QK A 501 43.697 50.453 15.048 1.00 87.52 O HETATM 2625 CAK 0QK A 501 44.059 49.550 12.875 1.00 83.19 C HETATM 2626 NAG 0QK A 501 45.066 48.488 13.030 1.00 85.72 N HETATM 2627 CAH 0QK A 501 46.402 48.539 13.094 1.00 75.33 C HETATM 2628 CAI 0QK A 501 46.818 47.278 13.227 1.00 79.57 C HETATM 2629 N3 0QK A 501 43.426 46.682 13.094 1.00 80.58 N HETATM 2630 N1 0QK A 501 44.422 44.529 13.334 1.00 85.54 N HETATM 2631 NAJ 0QK A 501 46.739 44.408 13.492 1.00 87.83 N HETATM 2632 S SO4 A 502 20.908 47.709 2.769 1.00 147.51 S HETATM 2633 O1 SO4 A 502 22.046 46.779 2.589 1.00 138.31 O HETATM 2634 O2 SO4 A 502 20.394 47.632 4.158 1.00 138.37 O HETATM 2635 O3 SO4 A 502 21.370 49.089 2.494 1.00 153.96 O HETATM 2636 O4 SO4 A 502 19.837 47.343 1.810 1.00 146.31 O HETATM 2637 S SO4 A 503 25.969 49.694 −12.194 1.00 132.72 S HETATM 2638 O1 SO4 A 503 26.217 51.050 −11.657 1.00 126.36 O HETATM 2639 O2 SO4 A 503 24.893 49.025 −11.419 1.00 128.90 O HETATM 2640 O3 SO4 A 503 25.555 49.841 −13.609 1.00 131.79 O HETATM 2641 O4 SO4 A 503 27.221 48.897 −12.107 1.00 142.06 O HETATM 2642 S SO4 A 504 32.612 58.455 −12.636 1.00 132.38 S HETATM 2643 O1 SO4 A 504 33.933 58.779 −13.242 1.00 126.62 O HETATM 2644 O2 SO4 A 504 32.606 57.112 −11.998 1.00 124.19 O HETATM 2645 O3 SO4 A 504 32.233 59.462 −11.609 1.00 129.55 O HETATM 2646 O4 SO4 A 504 31.611 58.453 −13.723 1.00 141.87 O HETATM 2647 O HOH A 601 37.950 51.247 5.661 1.00 74.64 O HETATM 2648 O HOH A 602 44.972 49.662 5.632 1.00 76.63 O HETATM 2649 O HOH A 603 46.338 36.042 10.941 1.00 99.98 O HETATM 2650 O HOH A 604 29.538 68.837 3.073 1.00 73.72 O HETATM 2651 O HOH A 605 42.475 33.970 16.341 1.00 86.94 O HETATM 2652 O HOH A 606 41.258 49.594 22.130 1.00 83.68 O HETATM 2653 O HOH A 607 40.197 52.386 20.536 1.00 103.60 O HETATM 2654 O HOH A 608 53.740 35.223 13.209 1.00 71.42 O HETATM 2655 O HOH A 609 15.616 84.733 7.777 1.00 75.14 O HETATM 2656 O HOH A 610 21.592 63.491 12.419 1.00 76.55 O CONECT 2593 2629 2630 CONECT 2594 2595 2626 2629 CONECT 2595 2594 2596 2628 CONECT 2596 2595 2630 2631 CONECT 2597 2598 CONECT 2598 2597 2599 2600 2601 CONECT 2599 2598 CONECT 2600 2598 CONECT 2601 2598 2602 2604 CONECT 2602 2601 2603 CONECT 2603 2602 2606 CONECT 2604 2601 2605 CONECT 2605 2604 2606 CONECT 2606 2603 2605 2607 CONECT 2607 2606 2608 CONECT 2608 2607 2609 2610 CONECT 2609 2608 CONECT 2610 2608 2611 CONECT 2611 2610 2612 CONECT 2612 2611 2613 CONECT 2613 2612 2614 CONECT 2614 2613 2615 2618 CONECT 2615 2614 2616 2617 CONECT 2616 2615 CONECT 2617 2615 CONECT 2618 2614 2619 CONECT 2619 2618 2620 2621 CONECT 2620 2619 2625 CONECT 2621 2619 2622 2623 CONECT 2622 2621 CONECT 2623 2621 2624 2625 CONECT 2624 2623 CONECT 2625 2620 2623 2626 CONECT 2626 2594 2625 2627 CONECT 2627 2626 2628 CONECT 2628 2595 2627 CONECT 2629 2593 2594 CONECT 2630 2593 2596 CONECT 2631 2596 CONECT 2632 2633 2634 2635 2636 CONECT 2633 2632 CONECT 2634 2632 CONECT 2635 2632 CONECT 2636 2632 CONECT 2637 2638 2639 2640 2641 CONECT 2638 2637 CONECT 2639 2637 CONECT 2640 2637 CONECT 2641 2637 CONECT 2642 2643 2644 2645 2646 CONECT 2643 2642 CONECT 2644 2642 CONECT 2645 2642 CONECT 2646 2642 MASTER 413 0 4 12 11 0 6 6 2655 1 54 33 END

TABLE S2 HEADER CRYSTAL STRUCTURE OF DOT1L IN COMPLEX WITH EPZ005676 CRYST1 154.326 154.326 47.524 90.00 90.00 120.00 P 65 SCALE1 0.006480 0.003741 0.000000 0.00000 SCALE2 0.000000 0.007482 0.000000 0.00000 SCALE3 0.000000 0.000000 0.021042 0.00000 ATOM 1 N LEU A 5 −58.657 −47.525 −16.411 1.00 107.90 A N ATOM 2 CA LEU A 5 −57.497 −47.204 −17.293 1.00 108.08 A C ATOM 3 CB LEU A 5 −57.628 −45.813 −17.948 1.00 108.27 A C ATOM 4 CG LEU A 5 −57.626 −44.504 −17.143 1.00 108.68 A C ATOM 5 CD1 LEU A 5 −57.194 −43.327 −18.026 1.00 108.80 A C ATOM 6 CD2 LEU A 5 −58.985 −44.238 −16.493 1.00 108.71 A C ATOM 7 C LEU A 5 −56.161 −47.350 −16.564 1.00 108.02 A C ATOM 8 O LEU A 5 −55.226 −47.936 −17.121 1.00 108.38 A O ATOM 9 N GLU A 6 −56.073 −46.819 −15.335 1.00 107.60 A N ATOM 10 CA GLU A 6 −54.887 −46.998 −14.459 1.00 106.72 A C ATOM 11 CB GLU A 6 −53.760 −45.991 −14.806 1.00 106.39 A C ATOM 12 CG GLU A 6 −54.106 −44.508 −14.639 1.00 106.96 A C ATOM 13 CD GLU A 6 −52.957 −43.552 −15.029 1.00 107.90 A C ATOM 14 OE1 GLU A 6 −52.841 −42.462 −14.423 1.00 107.84 A O ATOM 15 OE2 GLU A 6 −52.163 −43.878 −15.940 1.00 108.07 A O ATOM 16 C GLU A 6 −55.219 −47.030 −12.937 1.00 106.08 A C ATOM 17 O GLU A 6 −56.327 −46.658 −12.534 1.00 105.79 A O ATOM 18 N LEU A 7 −54.269 −47.529 −12.128 1.00 105.29 A N ATOM 19 CA LEU A 7 −54.295 −47.456 −10.645 1.00 104.13 A C ATOM 20 CB LEU A 7 −54.318 −48.851 −10.026 1.00 103.50 A C ATOM 21 CG LEU A 7 −55.428 −49.818 −10.455 1.00 103.26 A C ATOM 22 CD1 LEU A 7 −55.104 −51.250 −10.069 1.00 102.78 A C ATOM 23 CD2 LEU A 7 −56.791 −49.435 −9.894 1.00 103.03 A C ATOM 24 C LEU A 7 −53.080 −46.679 −10.111 1.00 103.90 A C ATOM 25 O LEU A 7 −51.986 −46.756 −10.673 1.00 104.05 A O ATOM 26 N ARG A 8 −53.261 −45.925 −9.033 1.00 103.54 A N ATOM 27 CA ARG A 8 −52.163 −45.108 −8.497 1.00 103.16 A C ATOM 28 CB ARG A 8 −52.354 −43.619 −8.836 1.00 103.46 A C ATOM 29 CG ARG A 8 −52.250 −43.281 −10.330 1.00 104.55 A C ATOM 30 CD ARG A 8 −52.146 −41.773 −10.599 1.00 105.28 A C ATOM 31 NE ARG A 8 −53.447 −41.117 −10.706 1.00 106.37 A N ATOM 32 CZ ARG A 8 −53.611 −39.806 −10.883 1.00 107.98 A C ATOM 33 NH1 ARG A 8 −52.550 −39.010 −10.983 1.00 108.55 A N ATOM 34 NH2 ARG A 8 −54.834 −39.282 −10.960 1.00 107.93 A N ATOM 35 C ARG A 8 −51.981 −45.273 −6.992 1.00 102.56 A C ATOM 36 O ARG A 8 −52.945 −45.202 −6.233 1.00 102.47 A O ATOM 37 N LEU A 9 −50.740 −45.496 −6.569 1.00 101.86 A N ATOM 38 CA LEU A 9 −50.417 −45.553 −5.145 1.00 101.12 A C ATOM 39 CB LEU A 9 −49.615 −46.818 −4.802 1.00 101.02 A C ATOM 40 CG LEU A 9 −50.212 −48.219 −5.004 1.00 100.46 A C ATOM 41 CD1 LEU A 9 −49.170 −49.260 −4.686 1.00 99.11 A C ATOM 42 CD2 LEU A 9 −51.468 −48.471 −4.174 1.00 100.38 A C ATOM 43 C LEU A 9 −49.626 −44.323 −4.733 1.00 100.72 A C ATOM 44 O LEU A 9 −48.577 −44.044 −5.308 1.00 100.61 A O ATOM 45 N LYS A 10 −50.127 −43.602 −3.733 1.00 100.19 A N ATOM 46 CA LYS A 10 −49.424 −42.445 −3.197 1.00 99.91 A C ATOM 47 CB LYS A 10 −50.378 −41.541 −2.410 1.00 99.74 A C ATOM 48 CG LYS A 10 −51.141 −40.512 −3.256 1.00 99.34 A C ATOM 49 CD LYS A 10 −52.305 −39.876 −2.477 1.00 98.37 A C ATOM 50 CE LYS A 10 −52.951 −38.690 −3.207 1.00 97.47 A C ATOM 51 NZ LYS A 10 −52.016 −37.565 −3.479 1.00 97.14 A N ATOM 52 C LYS A 10 −48.223 −42.856 −2.340 1.00 99.93 A C ATOM 53 O LYS A 10 −48.352 −43.628 −1.395 1.00 99.60 A O ATOM 54 N SER A 11 −47.053 −42.344 −2.705 1.00 100.23 A N ATOM 55 CA SER A 11 −45.827 −42.547 −1.950 1.00 100.78 A C ATOM 56 CB SER A 11 −44.690 −41.777 −2.607 1.00 100.77 A C ATOM 57 OG SER A 11 −43.759 −41.328 −1.641 1.00 100.49 A O ATOM 58 C SER A 11 −45.962 −42.108 −0.493 1.00 101.37 A C ATOM 59 O SER A 11 −46.535 −41.054 −0.219 1.00 101.58 A O ATOM 60 N PRO A 12 −45.418 −42.908 0.449 1.00 101.88 A N ATOM 61 CA PRO A 12 −45.658 −42.616 1.862 1.00 101.98 A C ATOM 62 CB PRO A 12 −45.233 −43.902 2.579 1.00 101.85 A C ATOM 63 CG PRO A 12 −44.284 −44.564 1.655 1.00 102.01 A C ATOM 64 CD PRO A 12 −44.663 −44.162 0.262 1.00 101.99 A C ATOM 65 C PRO A 12 −44.876 −41.428 2.375 1.00 102.13 A C ATOM 66 O PRO A 12 −45.253 −40.862 3.396 1.00 102.51 A O ATOM 67 N VAL A 13 −43.808 −41.042 1.690 1.00 102.24 A N ATOM 68 CA VAL A 13 −43.108 −39.813 2.068 1.00 102.61 A C ATOM 69 CB VAL A 13 −41.600 −40.023 2.336 1.00 102.51 A C ATOM 70 CG1 VAL A 13 −41.417 −41.035 3.458 1.00 102.63 A C ATOM 71 CG2 VAL A 13 −40.845 −40.439 1.057 1.00 102.51 A C ATOM 72 C VAL A 13 −43.367 −38.694 1.061 1.00 103.02 A C ATOM 73 O VAL A 13 −42.636 −37.689 1.018 1.00 103.28 A O ATOM 74 N GLY A 14 −44.429 −38.875 0.274 1.00 103.22 A N ATOM 75 CA GLY A 14 −44.871 −37.883 −0.697 1.00 103.31 A C ATOM 76 C GLY A 14 −43.917 −37.747 −1.866 1.00 103.50 A C ATOM 77 O GLY A 14 −43.369 −36.669 −2.100 1.00 103.60 A O ATOM 78 N ALA A 15 −43.699 −38.847 −2.583 1.00 103.51 A N ATOM 79 CA ALA A 15 −43.015 −38.804 −3.872 1.00 103.56 A C ATOM 80 CB ALA A 15 −41.936 −39.862 −3.949 1.00 103.62 A C ATOM 81 C ALA A 15 −44.010 −38.967 −5.019 1.00 103.54 A C ATOM 82 O ALA A 15 −45.210 −39.207 −4.792 1.00 103.39 A O ATOM 83 N GLU A 16 −43.500 −38.811 −6.243 1.00 103.52 A N ATOM 84 CA GLU A 16 −44.273 −39.033 −7.462 1.00 103.54 A C ATOM 85 CB GLU A 16 −43.415 −38.795 −8.717 1.00 103.40 A C ATOM 86 CG GLU A 16 −42.944 −37.337 −8.945 1.00 102.67 A C ATOM 87 CD GLU A 16 −44.083 −36.328 −9.111 0.50 101.57 A C ATOM 88 OE1 GLU A 16 −45.128 −36.658 −9.718 0.50 100.58 A O ATOM 89 OE2 GLU A 16 −43.918 −35.184 −8.638 0.50 101.23 A O ATOM 90 C GLU A 16 −44.834 −40.456 −7.434 1.00 103.74 A C ATOM 91 O GLU A 16 −44.073 −41.419 −7.362 1.00 103.99 A O ATOM 92 N PRO A 17 −46.170 −40.590 −7.463 1.00 103.87 A N ATOM 93 CA PRO A 17 −46.810 −41.862 −7.141 1.00 104.23 A C ATOM 94 CB PRO A 17 −48.311 −41.516 −7.184 1.00 104.08 A C ATOM 95 CG PRO A 17 −48.362 −40.057 −7.001 1.00 103.78 A C ATOM 96 CD PRO A 17 −47.175 −39.551 −7.737 1.00 103.72 A C ATOM 97 C PRO A 17 −46.492 −43.013 −8.104 1.00 104.50 A C ATOM 98 O PRO A 17 −46.070 −42.789 −9.239 1.00 104.69 A O ATOM 99 N ALA A 18 −46.693 −44.239 −7.639 1.00 104.74 A N ATOM 100 CA ALA A 18 −46.592 −45.389 −8.510 1.00 105.09 A C ATOM 101 CB ALA A 18 −46.379 −46.660 −7.713 1.00 105.05 A C ATOM 102 C ALA A 18 −47.861 −45.478 −9.323 1.00 105.42 A C ATOM 103 O ALA A 18 −48.960 −45.580 −8.767 1.00 105.44 A O ATOM 104 N VAL A 19 −47.692 −45.434 −10.642 1.00 105.93 A N ATOM 105 CA VAL A 19 −48.802 −45.519 −11.596 1.00 106.38 A C ATOM 106 CB VAL A 19 −48.698 −44.369 −12.649 1.00 106.45 A C ATOM 107 CG1 VAL A 19 −47.673 −44.686 −13.767 1.00 106.75 A C ATOM 108 CG2 VAL A 19 −50.062 −44.027 −13.210 1.00 106.40 A C ATOM 109 C VAL A 19 −48.872 −46.925 −12.229 1.00 106.29 A C ATOM 110 O VAL A 19 −47.834 −47.528 −12.490 1.00 106.37 A O ATOM 111 N TYR A 20 −50.081 −47.445 −12.444 1.00 106.39 A N ATOM 112 CA TYR A 20 −50.271 −48.846 −12.859 1.00 106.96 A C ATOM 113 CB TYR A 20 −50.663 −49.714 −11.664 1.00 106.95 A C ATOM 114 CG TYR A 20 −49.515 −50.151 −10.803 1.00 107.18 A C ATOM 115 CD1 TYR A 20 −48.901 −49.260 −9.928 1.00 107.84 A C ATOM 116 CE1 TYR A 20 −47.842 −49.650 −9.136 1.00 107.89 A C ATOM 117 CZ TYR A 20 −47.392 −50.948 −9.203 1.00 107.87 A C ATOM 118 OH TYR A 20 −46.347 −51.330 −8.399 1.00 108.59 A O ATOM 119 CE2 TYR A 20 −47.989 −51.857 −10.062 1.00 107.40 A C ATOM 120 CD2 TYR A 20 −49.047 −51.454 −10.851 1.00 106.94 A C ATOM 121 C TYR A 20 −51.314 −49.060 −13.953 1.00 107.46 A C ATOM 122 O TYR A 20 −52.514 −48.900 −13.706 1.00 107.44 A O ATOM 123 N PRO A 21 −50.866 −49.456 −15.160 1.00 107.88 A N ATOM 124 CA PRO A 21 −51.771 −49.671 −16.293 1.00 108.07 A C ATOM 125 CB PRO A 21 −50.811 −49.906 −17.466 1.00 108.11 A C ATOM 126 CG PRO A 21 −49.539 −49.245 −17.053 1.00 108.28 A C ATOM 127 CD PRO A 21 −49.458 −49.530 −15.578 1.00 108.10 A C ATOM 128 C PRO A 21 −52.671 −50.882 −16.098 1.00 108.13 A C ATOM 129 O PRO A 21 −52.241 −51.873 −15.519 1.00 108.33 A O ATOM 130 N TRP A 22 −53.912 −50.788 −16.568 1.00 108.25 A N ATOM 131 CA TRP A 22 −54.856 −51.905 −16.501 1.00 108.38 A C ATOM 132 CB TRP A 22 −56.138 −51.494 −15.771 1.00 108.38 A C ATOM 133 CG TRP A 22 −57.160 −52.560 −15.753 1.00 108.61 A C ATOM 134 CD1 TRP A 22 −58.068 −52.829 −16.725 1.00 109.81 A C ATOM 135 NE1 TRP A 22 −58.846 −53.901 −16.370 1.00 110.82 A N ATOM 136 CE2 TRP A 22 −58.439 −54.351 −15.144 1.00 110.32 A C ATOM 137 CD2 TRP A 22 −57.373 −53.527 −14.726 1.00 109.66 A C ATOM 138 CE3 TRP A 22 −56.770 −53.778 −13.492 1.00 110.30 A C ATOM 139 CZ3 TRP A 22 −57.247 −54.832 −12.724 1.00 110.81 A C ATOM 140 CH2 TRP A 22 −58.308 −55.633 −13.170 1.00 110.57 A C ATOM 141 CZ2 TRP A 22 −58.919 −55.407 −14.371 1.00 110.21 A C ATOM 142 C TRP A 22 −55.169 −52.433 −17.910 1.00 108.32 A C ATOM 143 O TRP A 22 −55.374 −51.635 −18.830 1.00 108.43 A O ATOM 144 N PRO A 23 −55.214 −53.772 −18.088 1.00 108.08 A N ATOM 145 CA PRO A 23 −55.095 −54.857 −17.108 1.00 107.88 A C ATOM 146 CB PRO A 23 −55.345 −56.105 −17.946 1.00 108.00 A C ATOM 147 CG PRO A 23 −54.820 −55.731 −19.284 1.00 108.15 A C ATOM 148 CD PRO A 23 −55.259 −54.305 −19.460 1.00 108.12 A C ATOM 149 C PRO A 23 −53.717 −54.940 −16.453 1.00 107.52 A C ATOM 150 O PRO A 23 −52.742 −54.415 −16.990 1.00 107.17 A O ATOM 151 N LEU A 24 −53.661 −55.610 −15.304 1.00 107.29 A N ATOM 152 CA LEU A 24 −52.480 −55.610 −14.446 1.00 106.83 A C ATOM 153 CB LEU A 24 −52.884 −55.772 −12.986 1.00 106.48 A C ATOM 154 CG LEU A 24 −53.299 −54.521 −12.246 1.00 105.13 A C ATOM 155 CD1 LEU A 24 −53.735 −54.969 −10.876 1.00 104.43 A C ATOM 156 CD2 LEU A 24 −52.154 −53.526 −12.188 1.00 102.73 A C ATOM 157 C LEU A 24 −51.521 −56.721 −14.800 1.00 106.92 A C ATOM 158 O LEU A 24 −51.786 −57.886 −14.482 1.00 107.12 A O ATOM 159 N PRO A 25 −50.378 −56.366 −15.410 1.00 106.73 A N ATOM 160 CA PRO A 25 −49.449 −57.374 −15.906 1.00 106.61 A C ATOM 161 CB PRO A 25 −48.194 −56.562 −16.222 1.00 106.29 A C ATOM 162 CG PRO A 25 −48.699 −55.188 −16.462 1.00 106.41 A C ATOM 163 CD PRO A 25 −49.808 −55.012 −15.498 1.00 106.57 A C ATOM 164 C PRO A 25 −49.127 −58.464 −14.881 1.00 106.57 A C ATOM 165 O PRO A 25 −49.016 −58.195 −13.686 1.00 106.47 A O ATOM 166 N VAL A 26 −49.037 −59.695 −15.363 1.00 106.67 A N ATOM 167 CA VAL A 26 −48.342 −60.738 −14.644 1.00 106.86 A C ATOM 168 CB VAL A 26 −49.089 −62.085 −14.724 1.00 106.84 A C ATOM 169 CG1 VAL A 26 −48.971 −62.703 −16.111 1.00 107.27 A C ATOM 170 CG2 VAL A 26 −48.582 −63.044 −13.653 1.00 107.27 A C ATOM 171 C VAL A 26 −46.910 −60.803 −15.216 1.00 106.94 A C ATOM 172 O VAL A 26 −46.716 −60.780 −16.445 1.00 107.11 A O ATOM 173 N TYR A 27 −45.921 −60.835 −14.321 1.00 106.65 A N ATOM 174 CA TYR A 27 −44.510 −60.833 −14.699 1.00 106.35 A C ATOM 175 CB TYR A 27 −43.688 −60.075 −13.656 1.00 106.33 A C ATOM 176 CG TYR A 27 −44.146 −58.660 −13.391 1.00 106.08 A C ATOM 177 CD1 TYR A 27 −43.888 −57.639 −14.305 1.00 106.87 A C ATOM 178 CE1 TYR A 27 −44.302 −56.330 −14.064 1.00 106.66 A C ATOM 179 CZ TYR A 27 −44.975 −56.036 −12.889 1.00 106.46 A C ATOM 180 OH TYR A 27 −45.389 −54.746 −12.648 1.00 106.52 A O ATOM 181 CE2 TYR A 27 −45.231 −57.031 −11.961 1.00 106.19 A C ATOM 182 CD2 TYR A 27 −44.809 −58.333 −12.213 1.00 106.23 A C ATOM 183 C TYR A 27 −43.938 −62.256 −14.907 1.00 106.44 A C ATOM 184 O TYR A 27 −43.043 −62.462 −15.752 1.00 106.21 A O ATOM 185 N ASP A 28 −44.454 −63.221 −14.142 1.00 106.21 A N ATOM 186 CA ASP A 28 −44.076 −64.626 −14.295 1.00 106.46 A C ATOM 187 CB ASP A 28 −42.673 −64.895 −13.719 1.00 106.76 A C ATOM 188 CG ASP A 28 −42.653 −64.993 −12.190 1.00 107.44 A C ATOM 189 OD1 ASP A 28 −43.368 −65.854 −11.626 1.00 106.45 A O ATOM 190 OD2 ASP A 28 −41.887 −64.224 −11.560 1.00 108.33 A O ATOM 191 C ASP A 28 −45.106 −65.569 −13.687 1.00 106.35 A C ATOM 192 O ASP A 28 −46.128 −65.130 −13.178 1.00 106.57 A O ATOM 193 N LYS A 29 −44.815 −66.864 −13.732 1.00 106.41 A N ATOM 194 CA LYS A 29 −45.693 −67.903 −13.195 1.00 106.83 A C ATOM 195 CB LYS A 29 −44.962 −69.259 −13.152 1.00 107.02 A C ATOM 196 CG LYS A 29 −45.886 −70.474 −13.192 1.00 107.71 A C ATOM 197 CD LYS A 29 −45.309 −71.671 −12.438 1.00 110.58 A C ATOM 198 CE LYS A 29 −44.155 −72.365 −13.176 1.00 112.07 A C ATOM 199 NZ LYS A 29 −43.588 −73.527 −12.403 1.00 111.84 A N ATOM 200 C LYS A 29 −46.229 −67.574 −11.802 1.00 106.81 A C ATOM 201 O LYS A 29 −47.380 −67.893 −11.483 1.00 106.90 A O ATOM 202 N HIS A 30 −45.385 −66.946 −10.981 1.00 106.73 A N ATOM 203 CA HIS A 30 −45.725 −66.632 −9.588 1.00 106.45 A C ATOM 204 CB HIS A 30 −44.874 −67.465 −8.620 1.00 106.54 A C ATOM 205 CG HIS A 30 −45.012 −68.946 −8.777 1.00 106.81 A C ATOM 206 ND1 HIS A 30 −46.235 −69.586 −8.804 1.00 107.56 A N ATOM 207 CE1 HIS A 30 −46.044 −70.888 −8.925 1.00 107.69 A C ATOM 208 NE2 HIS A 30 −44.742 −71.117 −8.960 1.00 107.78 A N ATOM 209 CD2 HIS A 30 −44.074 −69.919 −8.862 1.00 106.56 A C ATOM 210 C HIS A 30 −45.512 −65.161 −9.210 1.00 105.96 A C ATOM 211 O HIS A 30 −45.114 −64.891 −8.074 1.00 106.06 A O ATOM 212 N HIS A 31 −45.765 −64.219 −10.124 1.00 105.06 A N ATOM 213 CA HIS A 31 −45.543 −62.796 −9.821 1.00 104.23 A C ATOM 214 CB HIS A 31 −44.046 −62.439 −9.915 1.00 104.69 A C ATOM 215 CG HIS A 31 −43.211 −63.019 −8.810 1.00 106.26 A C ATOM 216 ND1 HIS A 31 −43.690 −63.202 −7.528 1.00 107.18 A N ATOM 217 CE1 HIS A 31 −42.744 −63.731 −6.775 1.00 107.46 A C ATOM 218 NE2 HIS A 31 −41.662 −63.885 −7.517 1.00 107.81 A N ATOM 219 CD2 HIS A 31 −41.925 −63.441 −8.790 1.00 107.42 A C ATOM 220 C HIS A 31 −46.372 −61.782 −10.617 1.00 103.01 A C ATOM 221 O HIS A 31 −45.881 −61.202 −11.575 1.00 102.92 A O ATOM 222 N ASP A 32 −47.612 −61.546 −10.188 1.00 101.71 A N ATOM 223 CA ASP A 32 −48.466 −60.514 −10.791 1.00 100.43 A C ATOM 224 CB ASP A 32 −49.965 −60.867 −10.709 1.00 100.67 A C ATOM 225 CG ASP A 32 −50.380 −61.445 −9.361 1.00 101.55 A C ATOM 226 CD1 ASP A 32 −49.615 −62.210 −8.738 1.00 102.97 A O ATOM 227 OD2 ASP A 32 −51.512 −61.165 −8.930 1.00 103.43 A O ATOM 228 C ASP A 32 −48.216 −59.135 −10.215 1.00 99.26 A C ATOM 229 O ASP A 32 −47.547 −58.985 −9.204 1.00 99.24 A O ATOM 230 N ALA A 33 −48.745 −58.123 −10.886 1.00 98.03 A N ATOM 231 CA ALA A 33 −48.656 −56.759 −10.391 1.00 96.77 A C ATOM 232 CB ALA A 33 −48.639 −55.757 −11.555 1.00 96.86 A C ATOM 233 C ALA A 33 −49.803 −56.475 −9.412 1.00 95.74 A C ATOM 234 O ALA A 33 −49.682 −55.618 −8.541 1.00 95.02 A O ATOM 235 N ALA A 34 −50.903 −57.217 −9.551 1.00 94.77 A N ATOM 236 CA ALA A 34 −51.979 −57.203 −8.556 1.00 93.89 A C ATOM 237 CB ALA A 34 −53.072 −58.173 −8.927 1.00 93.91 A C ATOM 238 C ALA A 34 −51.442 −57.540 −7.177 1.00 93.24 A C ATOM 239 O ALA A 34 −51.830 −56.935 −6.188 1.00 93.12 A O ATOM 240 N HIS A 35 −50.541 −58.508 −7.108 1.00 92.60 A N ATOM 241 CA HIS A 35 −49.945 −58.845 −5.832 1.00 91.83 A C ATOM 242 CB HIS A 35 −49.566 −60.324 −5.777 1.00 91.62 A C ATOM 243 CG HIS A 35 −50.731 −61.217 −5.481 0.50 90.57 A C ATOM 244 ND1 HIS A 35 −51.014 −62.346 −6.217 0.50 90.07 A N ATOM 245 CE1 HIS A 35 −52.104 −62.917 −5.739 0.50 89.92 A C ATOM 246 NE2 HIS A 35 −52.547 −62.192 −4.728 0.50 89.36 A N ATOM 247 CD2 HIS A 35 −51.707 −61.122 −4.548 0.50 89.45 A C ATOM 248 C HIS A 35 −48.806 −57.921 −5.427 1.00 91.42 A C ATOM 249 O HIS A 35 −48.578 −57.695 −4.239 1.00 91.03 A O ATOM 250 N GLU A 36 −48.129 −57.351 −6.417 1.00 91.18 A N ATOM 251 CA GLU A 36 −47.096 −56.360 −6.154 1.00 91.26 A C ATOM 252 CB GLU A 36 −46.556 −55.772 −7.477 1.00 91.13 A C ATOM 253 CG GLU A 36 −45.581 −54.591 −7.323 1.00 90.54 A C ATOM 254 CD GLU A 36 −44.818 −54.215 −8.604 1.00 89.75 A C ATOM 255 OE1 GLU A 36 −44.433 −55.096 −9.391 1.00 90.85 A O ATOM 256 OE2 GLU A 36 −44.556 −53.022 −8.816 1.00 88.99 A O ATOM 257 C GLU A 36 −47.718 −55.297 −5.256 1.00 91.50 A C ATOM 258 O GLU A 36 −47.150 −54.925 −4.234 1.00 90.95 A O ATOM 259 N ILE A 37 −48.918 −54.866 −5.654 1.00 92.17 A N ATOM 260 CA ILE A 37 −49.741 −53.870 −4.971 1.00 92.35 A C ATOM 261 CB ILE A 37 −51.102 −53.709 −5.700 1.00 92.24 A C ATOM 262 CG1 ILE A 37 −50.916 −53.184 −7.131 1.00 92.73 A C ATOM 263 CD1 ILE A 37 −50.160 −51.890 −7.261 1.00 93.34 A C ATOM 264 CG2 ILE A 37 −52.065 −52.845 −4.916 1.00 92.25 A C ATOM 265 C ILE A 37 −50.023 −54.293 −3.550 1.00 92.65 A C ATOM 266 O ILE A 37 −49.499 −53.714 −2.604 1.00 92.61 A O ATOM 267 N ILE A 38 −50.846 −55.320 −3.406 1.00 93.16 A N ATOM 268 CA ILE A 38 −51.246 −55.781 −2.095 1.00 93.96 A C ATOM 269 CB ILE A 38 −52.025 −57.110 −2.184 1.00 93.95 A C ATOM 270 CG1 ILE A 38 −53.388 −56.842 −2.831 1.00 93.67 A C ATOM 271 CD1 ILE A 38 −54.157 −58.067 −3.249 1.00 93.99 A C ATOM 272 CG2 ILE A 38 −52.219 −57.722 −0.801 1.00 94.33 A C ATOM 273 C ILE A 38 −50.068 −55.830 −1.106 1.00 94.55 A C ATOM 274 O ILE A 38 −50.228 −55.435 0.051 1.00 95.00 A O ATOM 275 N GLU A 39 −48.892 −56.264 −1.565 1.00 94.89 A N ATOM 276 CA GLU A 39 −47.697 −56.272 −0.720 1.00 95.14 A C ATOM 277 CB GLU A 39 −46.589 −57.137 −1.318 1.00 95.56 A C ATOM 278 CG GLU A 39 −46.921 −58.625 −1.454 1.00 98.10 A C ATOM 279 CD GLU A 39 −47.361 −59.267 −0.148 1.00 100.98 A C ATOM 280 OE1 GLU A 39 −47.984 −60.359 −0.196 1.00 101.55 A O ATOM 281 OE2 GLU A 39 −47.090 −58.676 0.924 1.00 102.90 A O ATOM 282 C GLU A 39 −47.169 −54.876 −0.482 1.00 94.82 A C ATOM 283 O GLU A 39 −46.984 −54.471 0.658 1.00 94.92 A O ATOM 284 N THR A 40 −46.930 −54.146 −1.568 1.00 95.00 A N ATOM 285 CA THR A 40 −46.428 −52.756 −1.518 1.00 94.85 A C ATOM 286 CB THR A 40 −46.570 −52.034 −2.904 1.00 94.57 A C ATOM 287 OG1 THR A 40 −46.216 −52.926 −3.963 1.00 93.63 A O ATOM 288 CG2 THR A 40 −45.692 −50.823 −2.988 1.00 93.55 A C ATOM 289 C THR A 40 −47.185 −51.972 −0.455 1.00 95.03 A C ATOM 290 O THR A 40 −46.605 −51.204 0.297 1.00 94.27 A O ATOM 291 N ILE A 41 −48.491 −52.195 −0.412 1.00 95.94 A N ATOM 292 CA ILE A 41 −49.348 −51.626 0.609 1.00 97.02 A C ATOM 293 CB ILE A 41 −50.852 −51.930 0.341 1.00 96.95 A C ATOM 294 CG1 ILE A 41 −51.299 −51.355 −1.008 1.00 96.41 A C ATOM 295 CD1 ILE A 41 −52.704 −51.772 −1.412 1.00 95.44 A C ATOM 296 CG2 ILE A 41 −51.727 −51.377 1.468 1.00 97.03 A C ATOM 297 C ILE A 41 −48.934 −52.140 1.989 1.00 97.75 A C ATOM 298 O ILE A 41 −48.401 −51.379 2.798 1.00 97.80 A O ATOM 299 N ARG A 42 −49.153 −53.432 2.233 1.00 98.52 A N ATOM 300 CA ARG A 42 −48.940 −54.033 3.551 1.00 99.77 A C ATOM 301 CB ARG A 42 −49.278 −55.521 3.509 1.00 100.23 A C ATOM 302 CG ARG A 42 −50.065 −55.999 4.719 1.00 103.05 A C ATOM 303 CD ARG A 42 −50.767 −57.324 4.416 1.00 108.82 A C ATOM 304 NE ARG A 42 −51.916 −57.587 5.294 1.00 112.94 A N ATOM 305 CZ ARG A 42 −51.868 −58.243 6.461 1.00 114.85 A C ATOM 306 NH1 ARG A 42 −52.993 −58.422 7.155 1.00 115.68 A N ATOM 307 NH2 ARG A 42 −50.715 −58.719 6.941 1.00 114.50 A N ATOM 308 C ARG A 42 −47.532 −53.820 4.126 1.00 99.80 A C ATOM 309 O ARG A 42 −47.319 −53.932 5.340 1.00 99.70 A O ATOM 310 N TRP A 43 −46.589 −53.510 3.245 1.00 99.95 A N ATOM 311 CA TRP A 43 −45.243 −53.160 3.641 1.00 100.55 A C ATOM 312 CB TRP A 43 −44.260 −53.439 2.495 1.00 100.67 A C ATOM 313 CG TRP A 43 −43.739 −54.835 2.541 1.00 100.81 A C ATOM 314 CD1 TRP A 43 −43.908 −55.813 1.604 1.00 99.76 A C ATOM 315 NE1 TRP A 43 −43.304 −56.972 2.018 1.00 99.31 A N ATOM 316 CE2 TRP A 43 −42.741 −56.766 3.251 1.00 100.88 A C ATOM 317 CD2 TRP A 43 −42.994 −55.428 3.613 1.00 101.34 A C ATOM 318 CE3 TRP A 43 −42.516 −54.953 4.849 1.00 100.31 A C ATOM 319 CZ3 TRP A 43 −41.815 −55.811 5.661 1.00 100.06 A C ATOM 320 CH2 TRP A 43 −41.579 −57.142 5.276 1.00 101.07 A C ATOM 321 CZ2 TRP A 43 −42.031 −57.638 4.078 1.00 101.17 A C ATOM 322 C TRP A 43 −45.127 −51.714 4.106 1.00 101.22 A C ATOM 323 O TRP A 43 −44.188 −51.358 4.818 1.00 101.16 A O ATOM 324 N VAL A 44 −46.069 −50.877 3.686 1.00 102.17 A N ATOM 325 CA VAL A 44 −46.094 −49.485 4.111 1.00 103.15 A C ATOM 326 CB VAL A 44 −46.727 −48.574 3.043 1.00 102.97 A C ATOM 327 CG1 VAL A 44 −46.855 −47.156 3.550 1.00 103.29 A C ATOM 328 CG2 VAL A 44 −45.874 −48.572 1.797 1.00 103.24 A C ATOM 329 C VAL A 44 −46.840 −49.420 5.438 1.00 104.12 A C ATOM 330 O VAL A 44 −46.401 −48.750 6.374 1.00 104.27 A O ATOM 331 N CYS A 45 −47.956 −50.145 5.508 1.00 105.17 A N ATOM 332 CA CYS A 45 −48.631 −50.450 6.757 1.00 106.25 A C ATOM 333 CB CYS A 45 −49.593 −51.611 6.541 1.00 106.20 A C ATOM 334 SG CYS A 45 −51.076 −51.211 5.617 1.00 106.20 A S ATOM 335 C CYS A 45 −47.640 −50.845 7.842 1.00 107.29 A C ATOM 336 O CYS A 45 −47.870 −50.597 9.021 1.00 107.60 A O ATOM 337 N GLU A 46 −46.545 −51.473 7.435 1.00 108.69 A N ATOM 338 CA GLU A 46 −45.515 −51.916 8.360 1.00 110.24 A C ATOM 339 CB GLU A 46 −44.612 −52.965 7.713 1.00 110.23 A C ATOM 340 CG GLU A 46 −45.138 −54.386 7.811 1.00 110.85 A C ATOM 341 CD GLU A 46 −44.997 −54.968 9.203 1.00 111.43 A C ATOM 342 OE1 GLU A 46 −44.313 −54.353 10.047 1.00 112.67 A O ATOM 343 OE2 GLU A 46 −45.575 −56.043 9.453 1.00 111.35 A O ATOM 344 C GLU A 46 −44.670 −50.787 8.917 1.00 111.35 A C ATOM 345 O GLU A 46 −44.439 −50.744 10.123 1.00 111.81 A O ATOM 346 N GLU A 47 −44.199 −49.887 8.053 1.00 112.63 A N ATOM 347 CA GLU A 47 −43.356 −48.777 8.498 1.00 114.09 A C ATOM 348 CB GLU A 47 −42.759 −48.016 7.323 1.00 114.16 A C ATOM 349 CG GLU A 47 −42.008 −48.818 6.296 1.00 115.52 A C ATOM 350 CD GLU A 47 −42.234 −48.247 4.902 1.00 117.58 A C ATOM 351 OE1 GLU A 47 −43.237 −48.643 4.268 1.00 118.42 A O ATOM 352 OE2 GLU A 47 −41.438 −47.390 4.449 1.00 117.72 A O ATOM 353 C GLU A 47 −44.158 −47.786 9.331 1.00 114.91 A C ATOM 354 O GLU A 47 −43.627 −47.144 10.241 1.00 115.34 A O ATOM 355 N ILE A 48 −45.432 −47.643 8.998 1.00 115.80 A N ATOM 356 CA ILE A 48 −46.292 −46.700 9.686 1.00 116.71 A C ATOM 357 CB ILE A 48 −47.101 −45.823 8.690 1.00 116.52 A C ATOM 358 CG1 ILE A 48 −46.208 −45.294 7.556 1.00 115.94 A C ATOM 359 CD1 ILE A 48 −45.167 −44.282 7.970 1.00 115.72 A C ATOM 360 CG2 ILE A 48 −47.856 −44.708 9.423 1.00 116.26 A C ATOM 361 C ILE A 48 −47.236 −47.452 10.629 1.00 117.74 A C ATOM 362 O ILE A 48 −48.272 −47.977 10.193 1.00 117.86 A O ATOM 363 N PRO A 49 −46.887 −47.500 11.930 1.00 118.61 A N ATOM 364 CA PRO A 49 −47.802 −48.069 12.916 1.00 119.18 A C ATOM 365 CB PRO A 49 −47.275 −47.512 14.246 1.00 119.38 A C ATOM 366 CG PRO A 49 −46.305 −46.392 13.863 1.00 119.07 A C ATOM 367 CD PRO A 49 −45.727 −46.862 12.577 1.00 118.70 A C ATOM 368 C PRO A 49 −49.228 −47.577 12.667 1.00 119.74 A C ATOM 369 O PRO A 49 −50.156 −48.387 12.601 1.00 119.68 A O ATOM 370 N ASP A 50 −49.374 −46.260 12.493 1.00 120.42 A N ATOM 371 CA ASP A 50 −50.673 −45.623 12.236 1.00 121.04 A C ATOM 372 CB ASP A 50 −50.536 −44.097 12.198 1.00 120.95 A C ATOM 373 CG ASP A 50 −50.319 −43.497 13.572 1.00 121.28 A C ATOM 374 OD1 ASP A 50 −50.936 −43.992 14.541 1.00 122.39 A O ATOM 375 OD2 ASP A 50 −49.540 −42.525 13.683 1.00 120.68 A O ATOM 376 C ASP A 50 −51.377 −46.112 10.971 1.00 121.39 A C ATOM 377 O ASP A 50 −52.587 −46.337 10.984 1.00 121.26 A O ATOM 378 N LEU A 51 −50.635 −46.275 9.879 1.00 121.82 A N ATOM 379 CA LEU A 51 −51.291 −46.624 8.632 1.00 122.30 A C ATOM 380 CB LEU A 51 −50.338 −46.623 7.437 1.00 122.31 A C ATOM 381 CG LEU A 51 −51.042 −46.766 6.079 1.00 122.00 A C ATOM 382 CD1 LEU A 51 −51.829 −45.526 5.728 1.00 121.37 A C ATOM 383 CD2 LEU A 51 −50.043 −47.072 4.989 1.00 122.10 A C ATOM 384 C LEU A 51 −52.013 −47.948 8.762 1.00 122.66 A C ATOM 385 O LEU A 51 −53.193 −48.027 8.453 1.00 122.67 A O ATOM 386 N LYS A 52 −51.318 −48.976 9.243 1.00 123.23 A N ATOM 387 CA LYS A 52 −51.953 −50.277 9.420 1.00 123.97 A C ATOM 388 CB LYS A 52 −50.941 −51.358 9.837 1.00 123.77 A C ATOM 389 CG LYS A 52 −51.479 −52.784 9.663 1.00 123.55 A C ATOM 390 CD LYS A 52 −50.397 −53.852 9.492 1.00 122.52 A C ATOM 391 CE LYS A 52 −51.038 −55.199 9.103 1.00 121.97 A C ATOM 392 NZ LYS A 52 −50.057 −56.277 8.787 1.00 120.64 A N ATOM 393 C LYS A 52 −53.088 −50.134 10.434 1.00 124.64 A C ATOM 394 O LYS A 52 −54.096 −50.856 10.372 1.00 124.65 A O ATOM 395 N LEU A 53 −52.918 −49.167 11.337 1.00 125.35 A N ATOM 396 CA LEU A 53 −53.910 −48.848 12.359 1.00 126.04 A C ATOM 397 CB LEU A 53 −53.290 −47.925 13.416 1.00 125.94 A C ATOM 398 CG LEU A 53 −53.937 −47.662 14.780 1.00 125.95 A C ATOM 399 CD1 LEU A 53 −54.465 −48.937 15.426 1.00 125.92 A C ATOM 400 CD2 LEU A 53 −52.940 −46.951 15.699 1.00 125.02 A C ATOM 401 C LEU A 53 −55.158 −48.226 11.737 1.00 126.53 A C ATOM 402 O LEU A 53 −56.265 −48.468 12.206 1.00 126.58 A O ATOM 403 N ALA A 54 −54.963 −47.441 10.675 1.00 127.36 A N ATOM 404 CA ALA A 54 −56.058 −46.870 9.875 1.00 127.99 A C ATOM 405 CB ALA A 54 −55.656 −45.516 9.330 1.00 127.67 A C ATOM 406 C ALA A 54 −56.465 −47.795 8.726 1.00 128.65 A C ATOM 407 O ALA A 54 −57.326 −47.447 7.915 1.00 128.47 A O ATOM 408 N MET A 55 −55.839 −48.972 8.667 1.00 129.68 A N ATOM 409 CA MET A 55 −56.079 −49.940 7.601 1.00 130.70 A C ATOM 410 CB MET A 55 −54.786 −50.201 6.815 1.00 130.51 A C ATOM 411 CG MET A 55 −54.384 −49.101 5.821 1.00 129.74 A C ATOM 412 SD MET A 55 −55.569 −48.795 4.492 1.00 127.39 A S ATOM 413 CE MET A 55 −55.325 −50.215 3.440 1.00 127.90 A C ATOM 414 C MET A 55 −56.671 −51.266 8.102 1.00 131.78 A C ATOM 415 O MET A 55 −56.973 −52.158 7.295 1.00 131.85 A O ATOM 416 N GLU A 56 −56.853 −51.387 9.422 1.00 133.02 A N ATOM 417 CA GLU A 56 −57.356 −52.631 10.045 1.00 134.07 A C ATOM 418 CB GLU A 56 −57.164 −52.596 11.570 1.00 134.37 A C ATOM 419 CG GLU A 56 −57.099 −53.987 12.225 1.00 135.95 A C ATOM 420 CD GLU A 56 −56.952 −53.938 13.743 1.00 137.82 A C ATOM 421 OE1 GLU A 56 −57.895 −54.388 14.438 1.00 138.95 A O ATOM 422 OE2 GLU A 56 −55.904 −53.454 14.241 1.00 138.31 A O ATOM 423 C GLU A 56 −58.819 −52.943 9.689 1.00 134.24 A C ATOM 424 O GLU A 56 −59.578 −53.476 10.512 1.00 134.24 A O ATOM 425 N ASN A 57 −59.190 −52.624 8.449 1.00 134.47 A N ATOM 426 CA ASN A 57 −60.555 −52.782 7.954 1.00 134.61 A C ATOM 427 CB ASN A 57 −61.045 −51.466 7.362 1.00 134.62 A C ATOM 428 CG ASN A 57 −60.630 −50.273 8.195 1.00 134.91 A C ATOM 429 OD1 ASN A 57 −61.277 −49.944 9.189 1.00 135.62 A O ATOM 430 ND2 ASN A 57 −59.540 −49.621 7.798 1.00 134.76 A N ATOM 431 C ASN A 57 −60.640 −53.893 6.919 1.00 134.61 A C ATOM 432 O ASN A 57 −61.608 −54.663 6.900 1.00 134.57 A O ATOM 433 N TYR A 58 −59.621 −53.955 6.059 1.00 134.64 A N ATOM 434 CA TYR A 58 −59.455 −55.038 5.085 1.00 134.67 A C ATOM 435 CB TYR A 58 −59.885 −54.602 3.672 1.00 134.65 A C ATOM 436 CG TYR A 58 −61.314 −54.090 3.576 1.00 134.28 A C ATOM 437 CD1 TYR A 58 −61.576 −52.720 3.476 1.00 133.84 A C ATOM 438 CE1 TYR A 58 −62.885 −52.239 3.392 1.00 133.72 A C ATOM 439 CZ TYR A 58 −63.949 −53.131 3.410 1.00 133.33 A C ATOM 440 OH TYR A 58 −65.239 −52.647 3.332 1.00 132.59 A O ATOM 441 CE2 TYR A 58 −63.716 −54.500 3.507 1.00 133.40 A C ATOM 442 CD2 TYR A 58 −62.401 −54.973 3.590 1.00 133.57 A C ATOM 443 C TYR A 58 −58.004 −55.513 5.073 1.00 134.65 A C ATOM 444 O TYR A 58 −57.075 −54.723 5.264 1.00 134.50 A O ATOM 445 N ILE A 61 −58.230 −60.096 2.529 1.00 148.19 A N ATOM 446 CA ILE A 61 −59.312 −60.854 1.913 1.00 148.20 A C ATOM 447 CB ILE A 61 −60.620 −59.970 1.823 1.00 148.39 A C ATOM 448 CG1 ILE A 61 −61.918 −60.819 1.881 1.00 148.59 A C ATOM 449 CD1 ILE A 61 −62.314 −61.569 0.604 1.00 149.13 A C ATOM 450 CG2 ILE A 61 −60.536 −58.923 0.686 1.00 148.44 A C ATOM 451 C ILE A 61 −58.885 −61.477 0.564 1.00 147.98 A C ATOM 452 O ILE A 61 −59.506 −62.438 0.098 1.00 148.04 A O ATOM 453 N ASP A 62 −57.792 −60.957 −0.013 1.00 147.69 A N ATOM 454 CA ASP A 62 −57.357 −61.249 −1.401 1.00 147.18 A C ATOM 455 CB ASP A 62 −56.754 −62.655 −1.557 1.00 147.32 A C ATOM 456 CG ASP A 62 −55.253 −62.683 −1.296 1.00 147.99 A C ATOM 457 OD1 ASP A 62 −54.859 −62.802 −0.119 1.00 148.20 A O ATOM 458 OD2 ASP A 62 −54.463 −62.613 −2.268 1.00 148.70 A O ATOM 459 C ASP A 62 −58.499 −61.030 −2.389 1.00 146.54 A C ATOM 460 O ASP A 62 −58.990 −61.977 −3.022 1.00 146.57 A O ATOM 461 N TYR A 63 −58.919 −59.772 −2.506 1.00 145.52 A N ATOM 462 CA TYR A 63 −60.147 −59.451 −3.212 1.00 144.43 A C ATOM 463 CB TYR A 63 −60.747 −58.128 −2.707 1.00 144.60 A C ATOM 464 CG TYR A 63 −62.252 −58.201 −2.506 1.00 144.65 A C ATOM 465 CD1 TYR A 63 −62.860 −59.383 −2.070 1.00 144.40 A C ATOM 466 CE1 TYR A 63 −64.235 −59.469 −1.897 1.00 144.58 A C ATOM 467 CZ TYR A 63 −65.027 −58.360 −2.149 1.00 145.01 A C ATOM 468 OH TYR A 63 −66.392 −58.445 −1.969 1.00 144.94 A O ATOM 469 CE2 TYR A 63 −64.451 −57.168 −2.577 1.00 145.08 A C ATOM 470 CD2 TYR A 63 −63.066 −57.095 −2.751 1.00 144.97 A C ATOM 471 C TYR A 63 −59.966 −59.481 −4.726 1.00 143.49 A C ATOM 472 O TYR A 63 −58.926 −59.074 −5.238 1.00 143.40 A O ATOM 473 N ASP A 64 −60.993 −59.987 −5.410 1.00 142.39 A N ATOM 474 CA ASP A 64 −61.014 −60.204 −6.866 1.00 141.30 A C ATOM 475 CB ASP A 64 −62.426 −59.996 −7.420 1.00 141.47 A C ATOM 476 CG ASP A 64 −63.438 −60.951 −6.804 1.00 141.89 A C ATOM 477 OD1 ASP A 64 −64.543 −60.491 −6.432 1.00 142.30 A O ATOM 478 OD2 ASP A 64 −63.122 −62.160 −6.678 1.00 141.76 A O ATOM 479 C ASP A 64 −59.996 −59.389 −7.644 1.00 140.30 A C ATOM 480 O ASP A 64 −60.279 −58.280 −8.104 1.00 140.13 A O ATOM 481 N THR A 65 −58.810 −59.972 −7.786 1.00 138.98 A N ATOM 482 CA THR A 65 −57.651 −59.287 −8.337 1.00 137.84 A C ATOM 483 CB THR A 65 −56.343 −60.030 −7.983 1.00 137.94 A C ATOM 484 OG1 THR A 65 −56.081 −61.041 −8.961 1.00 138.14 A O ATOM 485 CG2 THR A 65 −56.435 −60.677 −6.598 1.00 138.08 A C ATOM 486 C THR A 65 −57.752 −59.097 −9.851 1.00 136.91 A C ATOM 487 O THR A 65 −56.923 −58.414 −10.454 1.00 136.74 A O ATOM 488 N LYS A 66 −58.771 −59.706 −10.455 1.00 135.77 A N ATOM 489 CA LYS A 66 −59.036 −59.548 −11.887 1.00 134.47 A C ATOM 490 CB LYS A 66 −59.508 −60.876 −12.506 1.00 134.55 A C ATOM 491 CG LYS A 66 −58.377 −61.747 −13.098 1.00 134.51 A C ATOM 492 CD LYS A 66 −58.017 −61.360 −14.544 1.00 133.99 A C ATOM 493 CE LYS A 66 −57.176 −60.081 −14.628 1.00 133.79 A C ATOM 494 NZ LYS A 66 −57.313 −59.355 −15.926 1.00 133.20 A N ATOM 495 C LYS A 66 −60.020 −58.411 −12.193 1.00 133.48 A C ATOM 496 O LYS A 66 −60.388 −58.199 −13.351 1.00 133.37 A O ATOM 497 N SER A 67 −60.420 −57.681 −11.151 1.00 132.18 A N ATOM 498 CA SER A 67 −61.353 −56.561 −11.273 1.00 130.89 A C ATOM 499 CB SER A 67 −62.492 −56.716 −10.267 1.00 131.02 A C ATOM 500 OG SER A 67 −63.173 −55.483 −10.089 1.00 130.86 A O ATOM 501 C SER A 67 −60.688 −55.205 −11.060 1.00 129.93 A C ATOM 502 O SER A 67 −59.815 −55.064 −10.215 1.00 129.93 A O ATOM 503 N PHE A 68 −61.106 −54.210 −11.833 1.00 128.71 A N ATOM 504 CA PHE A 68 −60.701 −52.832 −11.579 1.00 127.56 A C ATOM 505 CB PHE A 68 −60.754 −52.005 −12.865 1.00 127.51 A C ATOM 506 CG PHE A 68 −60.508 −50.535 −12.657 1.00 126.77 A C ATOM 507 CD1 PHE A 68 −59.225 −50.013 −12.736 1.00 126.68 A C ATOM 508 CE1 PHE A 68 −58.995 −48.650 −12.553 1.00 126.24 A C ATOM 509 CZ PHE A 68 −60.057 −47.798 −12.280 1.00 125.65 A C ATOM 510 CE2 PHE A 68 −61.338 −48.308 −12.197 1.00 125.60 A C ATOM 511 CD2 PHE A 68 −61.560 −49.671 −12.389 1.00 126.17 A C ATOM 512 C PHE A 68 −61.644 −52.251 −10.535 1.00 126.83 A C ATOM 513 O PHE A 68 −61.224 −51.553 −9.613 1.00 126.82 A O ATOM 514 N GLU A 69 −62.925 −52.562 −10.696 1.00 125.85 A N ATOM 515 CA GLU A 69 −63.985 −52.135 −9.780 1.00 124.96 A C ATOM 516 CB GLU A 69 −65.349 −52.732 −10.216 1.00 125.21 A C ATOM 517 CG GLU A 69 −65.677 −52.671 −11.733 1.00 125.76 A C ATOM 518 CD GLU A 69 −65.053 −53.818 −12.551 1.00 126.64 A C ATOM 519 OE1 GLU A 69 −64.224 −53.533 −13.447 1.00 126.56 A O ATOM 520 OE2 GLU A 69 −65.387 −55.000 −12.299 1.00 126.55 A O ATOM 521 C GLU A 69 −63.675 −52.528 −8.322 1.00 123.89 A C ATOM 522 O GLU A 69 −64.465 −52.257 −7.413 1.00 123.86 A O ATOM 523 N SER A 70 −62.522 −53.158 −8.109 1.00 122.30 A N ATOM 524 CA SER A 70 −62.179 −53.714 −6.818 1.00 120.96 A C ATOM 525 CB SER A 70 −62.380 −55.226 −6.851 1.00 120.95 A C ATOM 526 OG SER A 70 −62.289 −55.789 −5.560 1.00 121.35 A O ATOM 527 C SER A 70 −60.745 −53.374 −6.422 1.00 120.04 A C ATOM 528 O SER A 70 −60.439 −53.207 −5.240 1.00 119.98 A O ATOM 529 N MET A 71 −59.866 −53.280 −7.412 1.00 118.79 A N ATOM 530 CA MET A 71 −58.463 −52.977 −7.159 1.00 117.61 A C ATOM 531 CB MET A 71 −57.576 −53.543 −8.271 1.00 117.56 A C ATOM 532 CG MET A 71 −57.391 −55.068 −8.245 1.00 116.29 A C ATOM 533 SD MET A 71 −56.669 −55.748 −6.732 1.00 113.64 A S ATOM 534 CE MET A 71 −55.114 −54.860 −6.643 1.00 112.92 A C ATOM 535 C MET A 71 −58.259 −51.475 −7.012 1.00 117.17 A C ATOM 536 O MET A 71 −57.283 −51.019 −6.420 1.00 116.71 A O ATOM 537 N GLN A 72 −59.191 −50.714 −7.572 1.00 116.80 A N ATOM 538 CA GLN A 72 −59.270 −49.286 −7.329 1.00 116.52 A C ATOM 539 CB GLN A 72 −60.106 −48.623 −8.424 1.00 116.59 A C ATOM 540 CG GLN A 72 −59.881 −47.128 −8.588 1.00 117.08 A C ATOM 541 CD GLN A 72 −61.111 −46.409 −9.136 1.00 118.53 A C ATOM 542 OE1 GLN A 72 −62.196 −46.995 −9.267 1.00 118.51 A O ATOM 543 NE2 GLN A 72 −60.948 −45.125 −9.446 1.00 119.22 A N ATOM 544 C GLN A 72 −59.915 −49.080 −5.956 1.00 116.11 A C ATOM 545 O GLN A 72 −59.471 −48.246 −5.152 1.00 115.82 A O ATOM 546 N ARG A 73 −60.950 −49.875 −5.691 1.00 115.62 A N ATOM 547 CA ARG A 73 −61.693 −49.802 −4.441 1.00 115.33 A C ATOM 548 CB ARG A 73 −62.965 −50.658 −4.531 1.00 115.64 A C ATOM 549 CG ARG A 73 −64.200 −50.065 −3.826 1.00 117.14 A C ATOM 550 CD ARG A 73 −65.496 −50.844 −4.136 1.00 119.28 A C ATOM 551 NE ARG A 73 −65.366 −52.268 −3.819 1.00 122.02 A N ATOM 552 CZ ARG A 73 −66.206 −53.225 −4.217 1.00 123.79 A C ATOM 553 NH1 ARG A 73 −67.270 −52.921 −4.957 1.00 124.79 A N ATOM 554 NH2 ARG A 73 −65.977 −54.496 −3.874 1.00 123.72 A N ATOM 555 C ARG A 73 −60.825 −50.221 −3.250 1.00 114.60 A C ATOM 556 O ARG A 73 −61.312 −50.310 −2.120 1.00 114.81 A O ATOM 557 N LEU A 74 −59.542 −50.472 −3.517 1.00 113.56 A N ATOM 558 CA LEU A 74 −58.548 −50.772 −2.483 1.00 112.50 A C ATOM 559 CB LEU A 74 −57.975 −52.183 −2.671 1.00 112.27 A C ATOM 560 CG LEU A 74 −56.625 −52.539 −2.031 1.00 111.68 A C ATOM 561 CD1 LEU A 74 −56.709 −52.637 −0.512 1.00 111.80 A C ATOM 562 CD2 LEU A 74 −56.106 −53.829 −2.597 1.00 110.94 A C ATOM 563 C LEU A 74 −57.425 −49.737 −2.489 1.00 112.02 A C ATOM 564 O LEU A 74 −56.933 −49.335 −1.438 1.00 111.93 A O ATOM 565 N CYS A 75 −57.016 −49.319 −3.677 1.00 111.48 A N ATOM 566 CA CYS A 75 −55.961 −48.338 −3.806 1.00 111.08 A C ATOM 567 CB CYS A 75 −55.688 −48.051 −5.272 1.00 111.07 A C ATOM 568 SG CYS A 75 −54.815 −49.361 −6.060 1.00 110.05 A S ATOM 569 C CYS A 75 −56.325 −47.053 −3.101 1.00 111.15 A C ATOM 570 O CYS A 75 −55.531 −46.517 −2.337 1.00 111.18 A O ATOM 571 N ASP A 76 −57.531 −46.561 −3.368 1.00 111.26 A N ATOM 572 CA ASP A 76 −58.008 −45.313 −2.774 1.00 111.06 A C ATOM 573 CB ASP A 76 −59.288 −44.831 −3.461 1.00 111.36 A C ATOM 574 CG ASP A 76 −59.208 −44.933 −4.977 1.00 111.91 A C ATOM 575 OD1 ASP A 76 −58.151 −44.566 −5.549 1.00 112.24 A O ATOM 576 OD2 ASP A 76 −60.205 −45.384 −5.586 1.00 112.26 A O ATOM 577 C ASP A 76 −58.220 −45.487 −1.283 1.00 110.53 A C ATOM 578 O ASP A 76 −57.856 −44.613 −0.513 1.00 110.53 A O ATOM 579 N LYS A 77 −58.781 −46.625 −0.880 1.00 109.92 A N ATOM 580 CA LYS A 77 −58.816 −46.993 0.526 1.00 109.58 A C ATOM 581 CB LYS A 77 −59.188 −48.465 0.684 1.00 109.53 A C ATOM 582 CG LYS A 77 −59.979 −48.772 1.945 1.00 110.76 A C ATOM 583 CD LYS A 77 −59.103 −48.936 3.197 1.00 112.28 A C ATOM 584 CE LYS A 77 −59.903 −48.725 4.493 1.00 113.11 A C ATOM 585 NZ LYS A 77 −61.147 −49.565 4.594 1.00 113.39 A N ATOM 586 C LYS A 77 −57.455 −46.702 1.172 1.00 109.25 A C ATOM 587 O LYS A 77 −57.389 −46.067 2.222 1.00 109.34 A O ATOM 588 N TYR A 78 −56.382 −47.150 0.522 1.00 108.83 A N ATOM 589 CA TYR A 78 −55.015 −46.878 0.959 1.00 108.46 A C ATOM 590 CB TYR A 78 −54.036 −47.844 0.268 1.00 108.12 A C ATOM 591 CG TYR A 78 −52.618 −47.325 0.098 1.00 106.86 A C ATOM 592 CD1 TYR A 78 −51.616 −47.659 1.009 1.00 105.78 A C ATOM 593 CE1 TYR A 78 −50.307 −47.177 0.855 1.00 104.19 A C ATOM 594 CZ TYR A 78 −49.996 −46.365 −0.221 1.00 103.25 A C ATOM 595 OH TYR A 78 −48.721 −45.894 −0.377 1.00 101.64 A O ATOM 596 CE2 TYR A 78 −50.970 −46.017 −1.137 1.00 104.51 A C ATOM 597 CD2 TYR A 78 −52.273 −46.504 −0.980 1.00 105.78 A C ATOM 598 C TYR A 78 −54.612 −45.423 0.704 1.00 108.79 A C ATOM 599 O TYR A 78 −54.011 −44.782 1.565 1.00 108.98 A O ATOM 600 N ASN A 79 −54.927 −44.909 −0.483 1.00 109.03 A N ATOM 601 CA ASN A 79 −54.532 −43.551 −0.872 1.00 109.17 A C ATOM 602 CB ASN A 79 −54.911 −43.273 −2.326 1.00 109.16 A C ATOM 603 CG ASN A 79 −53.888 −43.788 −3.296 1.00 108.66 A C ATOM 604 OD1 ASN A 79 −52.823 −43.204 −3.452 1.00 108.38 A O ATOM 605 ND2 ASN A 79 −54.208 −44.883 −3.965 1.00 108.29 A N ATOM 606 C ASN A 79 −55.137 −42.478 0.024 1.00 109.32 A C ATOM 607 O ASN A 79 −54.520 −41.436 0.266 1.00 109.26 A O ATOM 608 N ARG A 80 −56.352 −42.746 0.498 1.00 109.42 A N ATOM 609 CA ARG A 80 −57.021 −41.887 1.461 1.00 109.53 A C ATOM 610 CB ARG A 80 −58.486 −42.304 1.651 1.00 109.47 A C ATOM 611 CG ARG A 80 −59.354 −42.115 0.427 1.00 109.65 A C ATOM 612 CD ARG A 80 −60.823 −42.087 0.778 1.00 110.68 A C ATOM 613 NE ARG A 80 −61.471 −43.396 0.758 1.00 111.79 A N ATOM 614 CZ ARG A 80 −61.977 −43.973 −0.331 1.00 112.65 A C ATOM 615 NH1 ARG A 80 −61.891 −43.370 −1.516 1.00 113.21 A N ATOM 616 NH2 ARG A 80 −62.562 −45.163 −0.238 1.00 112.70 A N ATOM 617 C ARG A 80 −56.262 −41.986 2.774 1.00 109.55 A C ATOM 618 O ARG A 80 −55.782 −40.975 3.310 1.00 109.50 A O ATOM 619 N ALA A 81 −56.137 −43.219 3.260 1.00 109.52 A N ATOM 620 CA ALA A 81 −55.428 −43.514 4.492 1.00 109.61 A C ATOM 621 CB ALA A 81 −55.173 −45.003 4.596 1.00 109.59 A C ATOM 622 C ALA A 81 −54.123 −42.727 4.593 1.00 109.65 A C ATOM 623 O ALA A 81 −53.861 −42.082 5.606 1.00 109.66 A O ATOM 624 N ILE A 82 −53.335 −42.758 3.525 1.00 109.87 A N ATOM 625 CA ILE A 82 −52.070 −42.032 3.458 1.00 110.27 A C ATOM 626 CB ILE A 82 −51.390 −42.233 2.086 1.00 110.13 A C ATOM 627 CG1 ILE A 82 −50.775 −43.631 2.008 1.00 110.39 A C ATOM 628 CD1 ILE A 82 −49.630 −43.881 2.984 1.00 110.23 A C ATOM 629 CG2 ILE A 82 −50.324 −41.176 1.821 1.00 109.85 A C ATOM 630 C ILE A 82 −52.227 −40.550 3.763 1.00 110.67 A C ATOM 631 O ILE A 82 −51.499 −40.001 4.589 1.00 110.56 A O ATOM 632 N ASP A 83 −53.182 −39.909 3.099 1.00 111.41 A N ATOM 633 CA ASP A 83 −53.382 −38.481 3.266 1.00 112.09 A C ATOM 634 CB ASP A 83 −54.531 −37.987 2.384 1.00 111.72 A C ATOM 635 CG ASP A 83 −54.178 −37.996 0.898 1.00 111.20 A C ATOM 636 OD1 ASP A 83 −53.023 −37.679 0.524 1.00 109.51 A O ATOM 637 OD2 ASP A 83 −55.071 −38.318 0.095 1.00 111.13 A O ATOM 638 C ASP A 83 −53.630 −38.198 4.734 1.00 112.82 A C ATOM 639 O ASP A 83 −52.987 −37.333 5.332 1.00 112.77 A O ATOM 640 N SER A 84 −54.528 −38.982 5.318 1.00 113.99 A N ATOM 641 CA SER A 84 −54.825 −38.896 6.735 1.00 115.04 A C ATOM 642 CB SER A 84 −55.782 −40.003 7.159 1.00 114.86 A C ATOM 643 OG SER A 84 −56.097 −39.858 8.526 1.00 115.17 A O ATOM 644 C SER A 84 −53.561 −38.940 7.580 1.00 115.81 A C ATOM 645 O SER A 84 −53.458 −38.212 8.556 1.00 116.25 A O ATOM 646 N ILE A 85 −52.600 −39.779 7.209 1.00 116.79 A N ATOM 647 CA ILE A 85 −51.319 −39.798 7.917 1.00 117.76 A C ATOM 648 CB ILE A 85 −50.387 −40.972 7.477 1.00 117.66 A C ATOM 649 CG1 ILE A 85 −51.134 −42.305 7.423 1.00 117.67 A C ATOM 650 CD1 ILE A 85 −51.749 −42.753 8.737 1.00 118.16 A C ATOM 651 CG2 ILE A 85 −49.181 −41.085 8.400 1.00 117.67 A C ATOM 652 C ILE A 85 −50.591 −38.478 7.688 1.00 118.51 A C ATOM 653 O ILE A 85 −50.081 −37.875 8.628 1.00 118.56 A O ATOM 654 N HIS A 86 −50.559 −38.033 6.435 1.00 119.49 A N ATOM 655 CA HIS A 86 −49.768 −36.872 6.062 1.00 120.42 A C ATOM 656 CB HIS A 86 −49.645 −36.755 4.553 1.00 120.44 A C ATOM 657 CG HIS A 86 −48.533 −37.576 3.997 1.00 120.44 A C ATOM 658 ND1 HIS A 86 −48.749 −38.739 3.295 1.00 120.34 A N ATOM 659 CE1 HIS A 86 −47.587 −39.262 2.949 1.00 120.27 A C ATOM 660 NE2 HIS A 86 −46.624 −38.489 3.419 1.00 120.05 A N ATOM 661 CD2 HIS A 86 −47.190 −37.429 4.081 1.00 120.58 A C ATOM 662 C HIS A 86 −50.306 −35.597 6.643 1.00 121.22 A C ATOM 663 O HIS A 86 −49.544 −34.660 6.876 1.00 121.40 A O ATOM 664 N GLN A 87 −51.615 −35.560 6.877 1.00 122.16 A N ATOM 665 CA GLN A 87 −52.204 −34.462 7.629 1.00 123.16 A C ATOM 666 CB GLN A 87 −53.743 −34.520 7.633 1.00 123.21 A C ATOM 667 CG GLN A 87 −54.441 −33.836 6.427 1.00 122.96 A C ATOM 668 CD GLN A 87 −53.996 −32.384 6.176 1.00 122.88 A C ATOM 669 OE1 GLN A 87 −53.924 −31.565 7.092 1.00 122.57 A O ATOM 670 NE2 GLN A 87 −53.708 −32.068 4.922 1.00 123.70 A N ATOM 671 C GLN A 87 −51.632 −34.449 9.051 1.00 123.82 A C ATOM 672 O GLN A 87 −51.205 −33.405 9.540 1.00 123.82 A O ATOM 673 N LEU A 88 −51.588 −35.619 9.686 1.00 124.72 A N ATOM 674 CA LEU A 88 −51.017 −35.769 11.032 1.00 125.70 A C ATOM 675 CB LEU A 88 −51.103 −37.233 11.464 1.00 125.65 A C ATOM 676 CG LEU A 88 −51.652 −37.556 12.849 1.00 125.34 A C ATOM 677 CD1 LEU A 88 −52.315 −38.923 12.805 1.00 124.92 A C ATOM 678 CD2 LEU A 88 −50.557 −37.508 13.901 1.00 124.77 A C ATOM 679 C LEU A 88 −49.564 −35.262 11.130 1.00 126.40 A C ATOM 680 O LEU A 88 −49.204 −34.561 12.082 1.00 126.40 A O ATOM 681 N TRP A 89 −48.746 −35.612 10.139 1.00 127.23 A N ATOM 682 CA TRP A 89 −47.382 −35.098 10.017 1.00 128.22 A C ATOM 683 CB TRP A 89 −46.731 −35.612 8.722 1.00 128.29 A C ATOM 684 CG TRP A 89 −46.492 −37.123 8.620 1.00 128.38 A C ATOM 685 CD1 TRP A 89 −47.028 −38.108 9.406 1.00 128.56 A C ATOM 686 NE1 TRP A 89 −46.586 −39.341 8.992 1.00 127.79 A N ATOM 687 CE2 TRP A 89 −45.766 −39.180 7.906 1.00 128.02 A C ATOM 688 CD2 TRP A 89 −45.683 −37.797 7.640 1.00 128.22 A C ATOM 689 CE3 TRP A 89 −44.889 −37.363 6.565 1.00 128.31 A C ATOM 690 CZ3 TRP A 89 −44.214 −38.313 5.801 1.00 127.60 A C ATOM 691 CH2 TRP A 89 −44.317 −39.678 6.095 1.00 127.75 A C ATOM 692 CZ2 TRP A 89 −45.087 −40.133 7.138 1.00 128.08 A C ATOM 693 C TRP A 89 −47.342 −33.559 10.033 1.00 128.98 A C ATOM 694 O TRP A 89 −46.307 −32.968 10.341 1.00 128.91 A O ATOM 695 N LYS A 90 −48.464 −32.922 9.687 1.00 130.08 A N ATOM 696 CA LYS A 90 −48.595 −31.453 9.749 1.00 131.13 A C ATOM 697 CB LYS A 90 −49.674 −30.941 8.782 1.00 131.09 A C ATOM 698 CG LYS A 90 −49.407 −31.158 7.293 1.00 131.08 A C ATOM 699 CD LYS A 90 −50.525 −30.524 6.449 1.00 130.36 A C ATOM 700 CE LYS A 90 −50.416 −30.877 4.973 1.00 129.56 A C ATOM 701 NZ LYS A 90 −49.144 −30.412 4.359 1.00 129.04 A N ATOM 702 C LYS A 90 −48.897 −30.939 11.171 1.00 131.85 A C ATOM 703 O LYS A 90 −48.744 −29.744 11.445 1.00 131.78 A O ATOM 704 N GLY A 91 −49.345 −31.841 12.052 1.00 132.69 A N ATOM 705 CA GLY A 91 −49.537 −31.543 13.478 1.00 133.53 A C ATOM 706 C GLY A 91 −48.305 −31.927 14.281 1.00 134.21 A C ATOM 707 O GLY A 91 −47.279 −32.301 13.704 1.00 134.25 A O ATOM 708 N THR A 92 −48.400 −31.841 15.609 1.00 134.87 A N ATOM 709 CA THR A 92 −47.259 −32.142 16.494 1.00 135.45 A C ATOM 710 CB THR A 92 −47.515 −31.715 17.970 1.00 135.42 A C ATOM 711 OG1 THR A 92 −48.734 −32.309 18.441 1.00 135.55 A O ATOM 712 CG2 THR A 92 −47.588 −30.191 18.114 1.00 135.32 A C ATOM 713 C THR A 92 −46.908 −33.630 16.461 1.00 135.86 A C ATOM 714 O THR A 92 −47.334 −34.397 17.333 1.00 135.95 A O ATOM 715 N THR A 93 −46.148 −34.033 15.441 1.00 136.31 A N ATOM 716 CA THR A 93 −45.756 −35.440 15.253 1.00 136.73 A C ATOM 717 CB THR A 93 −46.895 −36.283 14.617 1.00 136.72 A C ATOM 718 OG1 THR A 93 −48.163 −35.804 15.078 1.00 137.36 A O ATOM 719 CG2 THR A 93 −46.754 −37.763 14.984 1.00 136.63 A C ATOM 720 C THR A 93 −44.486 −35.586 14.408 1.00 136.90 A C ATOM 721 O THR A 93 −44.057 −34.648 13.723 1.00 137.02 A O ATOM 722 N GLN A 94 −43.885 −36.770 14.469 1.00 136.99 A N ATOM 723 CA GLN A 94 −42.685 −37.050 13.701 1.00 137.09 A C ATOM 724 CB GLN A 94 −41.814 −38.105 14.406 1.00 137.35 A C ATOM 725 CG GLN A 94 −41.641 −37.906 15.938 1.00 138.27 A C ATOM 726 CD GLN A 94 −41.049 −36.543 16.334 1.00 139.15 A C ATOM 727 OE1 GLN A 94 −41.713 −35.506 16.239 1.00 139.01 A O ATOM 728 NE2 GLN A 94 −39.804 −36.554 16.806 1.00 139.46 A N ATOM 729 C GLN A 94 −43.073 −37.489 12.290 1.00 136.74 A C ATOM 730 O GLN A 94 −43.986 −38.308 12.121 1.00 136.67 A O ATOM 731 N PRO A 95 −42.388 −36.936 11.267 1.00 136.34 A N ATOM 732 CA PRO A 95 −42.684 −37.285 9.884 1.00 135.91 A C ATOM 733 CB PRO A 95 −41.927 −36.211 9.099 1.00 135.95 A C ATOM 734 CG PRO A 95 −40.738 −35.923 9.944 1.00 136.04 A C ATOM 735 CD PRO A 95 −41.250 −35.999 11.360 1.00 136.35 A C ATOM 736 C PRO A 95 −42.137 −38.671 9.538 1.00 135.52 A C ATOM 737 O PRO A 95 −41.684 −38.888 8.406 1.00 135.58 A O ATOM 738 N MET A 96 −42.196 −39.593 10.508 1.00 134.91 A N ATOM 739 CA MET A 96 −41.560 −40.914 10.422 1.00 134.21 A C ATOM 740 CB MET A 96 −42.149 −41.739 9.266 1.00 134.27 A C ATOM 741 CG MET A 96 −41.526 −43.121 9.058 1.00 134.39 A C ATOM 742 SD MET A 96 −41.574 −43.675 7.334 1.00 134.08 A S ATOM 743 CE MET A 96 −39.994 −43.078 6.730 1.00 134.28 A C ATOM 744 C MET A 96 −40.048 −40.747 10.267 1.00 133.67 A C ATOM 745 O MET A 96 −39.585 −39.908 9.487 1.00 133.79 A O ATOM 746 N LYS A 97 −39.278 −41.532 11.016 1.00 132.79 A N ATOM 747 CA LYS A 97 −37.822 −41.481 10.908 1.00 131.93 A C ATOM 748 CB LYS A 97 −37.185 −42.508 11.842 1.00 132.14 A C ATOM 749 CG LYS A 97 −35.725 −42.254 12.157 1.00 132.59 A C ATOM 750 CD LYS A 97 −35.136 −43.460 12.856 1.00 133.29 A C ATOM 751 CE LYS A 97 −33.637 −43.517 12.673 1.00 134.03 A C ATOM 752 NZ LYS A 97 −33.160 −44.923 12.769 1.00 134.53 A N ATOM 753 C LYS A 97 −37.447 −41.730 9.442 1.00 131.10 A C ATOM 754 O LYS A 97 −37.441 −42.878 8.971 1.00 131.23 A O ATOM 755 N LEU A 98 −37.160 −40.640 8.730 1.00 129.70 A N ATOM 756 CA LEU A 98 −37.130 −40.642 7.264 1.00 128.31 A C ATOM 757 CB LEU A 98 −37.201 −39.203 6.736 1.00 128.51 A C ATOM 758 CG LEU A 98 −38.009 −38.800 5.489 1.00 128.67 A C ATOM 759 CD1 LEU A 98 −37.679 −39.617 4.235 1.00 128.21 A C ATOM 760 CD2 LEU A 98 −39.521 −38.801 5.776 1.00 128.98 A C ATOM 761 C LEU A 98 −35.917 −41.353 6.668 1.00 127.13 A C ATOM 762 O LEU A 98 −36.054 −42.206 5.799 1.00 127.18 A O ATOM 763 N ASN A 99 −34.736 −41.010 7.157 1.00 125.50 A N ATOM 764 CA ASN A 99 −33.486 −41.373 6.501 1.00 124.11 A C ATOM 765 CB ASN A 99 −32.443 −40.270 6.777 1.00 124.45 A C ATOM 766 CG ASN A 99 −33.089 −38.895 7.120 1.00 125.14 A C ATOM 767 OD1 ASN A 99 −32.575 −38.141 7.962 1.00 125.15 A O ATOM 768 ND2 ASN A 99 −34.213 −38.579 6.469 1.00 125.28 A N ATOM 769 C ASN A 99 −32.964 −42.778 6.891 1.00 122.87 A C ATOM 770 O ASN A 99 −31.777 −42.954 7.191 1.00 122.66 A O ATOM 771 N THR A 100 −33.861 −43.768 6.864 1.00 121.29 A N ATOM 772 CA THR A 100 −33.572 −45.151 7.299 1.00 119.54 A C ATOM 773 CB THR A 100 −34.764 −45.792 8.075 1.00 119.58 A C ATOM 774 OG1 THR A 100 −35.989 −45.108 7.771 1.00 119.45 A O ATOM 775 CG2 THR A 100 −34.513 −45.751 9.567 1.00 119.76 A C ATOM 776 C THR A 100 −33.170 −46.148 6.205 1.00 118.22 A C ATOM 777 O THR A 100 −33.301 −45.888 5.010 1.00 118.24 A O ATOM 778 N ARG A 101 −32.668 −47.292 6.654 1.00 116.43 A N ATOM 779 CA ARG A 101 −32.426 −48.447 5.811 1.00 114.67 A C ATOM 780 CB ARG A 101 −31.170 −49.191 6.286 1.00 114.86 A C ATOM 781 CG ARG A 101 −30.006 −49.182 5.293 1.00 115.67 A C ATOM 782 CD ARG A 101 −28.679 −49.571 5.947 1.00 117.54 A C ATOM 783 NE ARG A 101 −27.978 −48.388 6.455 1.00 119.64 A N ATOM 784 CZ ARG A 101 −26.864 −47.875 5.933 1.00 120.21 A C ATOM 785 NH1 ARG A 101 −26.284 −48.450 4.886 1.00 121.18 A N ATOM 786 NH2 ARG A 101 −26.320 −46.786 6.465 1.00 120.14 A N ATOM 787 C ARG A 101 −33.651 −49.363 5.878 1.00 113.12 A C ATOM 788 O ARG A 101 −34.383 −49.354 6.878 1.00 113.26 A O ATOM 789 N PRO A 102 −33.892 −50.152 4.813 1.00 111.37 A N ATOM 790 CA PRO A 102 −35.006 −51.089 4.851 1.00 110.03 A C ATOM 791 CB PRO A 102 −34.992 −51.702 3.445 1.00 109.91 A C ATOM 792 CG PRO A 102 −34.236 −50.756 2.620 1.00 110.25 A C ATOM 793 CD PRO A 102 −33.206 −50.187 3.511 1.00 111.07 A C ATOM 794 C PRO A 102 −34.790 −52.188 5.880 1.00 108.68 A C ATOM 795 O PRO A 102 −33.662 −52.521 6.201 1.00 108.59 A O ATOM 796 N SER A 103 −35.869 −52.751 6.394 1.00 107.44 A N ATOM 797 CA SER A 103 −35.766 −53.992 7.124 1.00 106.19 A C ATOM 798 CB SER A 103 −37.127 −54.413 7.655 1.00 106.13 A C ATOM 799 OG SER A 103 −37.917 −54.955 6.621 1.00 105.32 A O ATOM 800 C SER A 103 −35.284 −54.985 6.092 1.00 105.65 A C ATOM 801 O SER A 103 −35.193 −54.641 4.917 1.00 105.94 A O ATOM 802 N THR A 104 −34.964 −56.208 6.505 1.00 104.80 A N ATOM 803 CA THR A 104 −34.550 −57.217 5.540 1.00 103.43 A C ATOM 804 CB THR A 104 −33.938 −58.449 6.212 1.00 103.59 A C ATOM 805 OG1 THR A 104 −32.761 −58.050 6.927 1.00 103.63 A O ATOM 806 CG2 THR A 104 −33.562 −59.508 5.165 1.00 103.73 A C ATOM 807 C THR A 104 −35.758 −57.576 4.707 1.00 102.27 A C ATOM 808 O THR A 104 −35.766 −57.361 3.498 1.00 102.12 A O ATOM 809 N GLY A 105 −36.796 −58.055 5.380 1.00 101.17 A N ATOM 810 CA GLY A 105 −38.044 −58.457 4.731 1.00 100.14 A C ATOM 811 C GLY A 105 −38.594 −57.528 3.658 1.00 99.09 A C ATOM 812 O GLY A 105 −39.199 −57.986 2.684 1.00 98.91 A O ATOM 813 N LEU A 106 −38.390 −56.226 3.848 1.00 98.09 A N ATOM 814 CA LEU A 106 −38.909 −55.211 2.945 1.00 97.14 A C ATOM 815 CB LEU A 106 −39.000 −53.844 3.646 1.00 97.05 A C ATOM 816 CG LEU A 106 −38.844 −52.519 2.879 1.00 96.66 A C ATOM 817 CD1 LEU A 106 −39.996 −52.247 1.904 1.00 96.43 A C ATOM 818 CD2 LEU A 106 −38.709 −51.372 3.854 1.00 95.77 A C ATOM 819 C LEU A 106 −38.023 −55.133 1.729 1.00 96.62 A C ATOM 820 O LEU A 106 −38.520 −55.042 0.610 1.00 96.72 A O ATOM 821 N LEU A 107 −36.713 −55.168 1.946 1.00 95.85 A N ATOM 822 CA LEU A 107 −35.786 −55.095 0.837 1.00 95.18 A C ATOM 823 CB LEU A 107 −34.334 −55.050 1.304 1.00 94.92 A C ATOM 824 CG LEU A 107 −33.319 −54.998 0.153 1.00 93.56 A C ATOM 825 CD1 LEU A 107 −33.530 −53.763 −0.687 1.00 92.18 A C ATOM 826 CD2 LEU A 107 −31.889 −55.072 0.649 1.00 92.76 A C ATOM 827 C LEU A 107 −36.000 −56.253 −0.129 1.00 95.10 A C ATOM 828 O LEU A 107 −35.792 −56.100 −1.326 1.00 95.33 A O ATOM 829 N ARG A 108 −36.426 −57.403 0.376 1.00 94.70 A N ATOM 830 CA ARG A 108 −36.740 −58.505 −0.516 1.00 94.78 A C ATOM 831 CB ARG A 108 −37.256 −59.716 0.263 1.00 95.07 A C ATOM 832 CG ARG A 108 −37.494 −60.979 −0.585 1.00 97.30 A C ATOM 833 CD ARG A 108 −37.690 −62.256 0.270 1.00 101.92 A C ATOM 834 NE ARG A 108 −38.029 −61.996 1.676 1.00 106.59 A N ATOM 835 CZ ARG A 108 −39.155 −61.414 2.117 1.00 110.59 A C ATOM 836 NH1 ARG A 108 −39.337 −61.240 3.425 1.00 112.80 A N ATOM 837 NH2 ARG A 108 −40.102 −60.987 1.274 1.00 111.51 A N ATOM 838 C ARG A 108 −37.762 −58.010 −1.532 1.00 94.14 A C ATOM 839 O ARG A 108 −37.521 −58.021 −2.744 1.00 94.26 A O ATOM 840 N HIS A 109 −38.882 −57.530 −1.012 1.00 93.50 A N ATOM 841 CA HIS A 109 −39.964 −56.987 −1.820 1.00 92.75 A C ATOM 842 CB HIS A 109 −41.027 −56.395 −0.897 1.00 92.37 A C ATOM 843 CG HIS A 109 −42.092 −55.621 −1.603 1.00 90.81 A C ATOM 844 ND1 HIS A 109 −43.233 −56.208 −2.100 1.00 89.32 A N ATOM 845 CE1 HIS A 109 −44.002 −55.280 −2.636 1.00 88.92 A C ATOM 846 NE2 HIS A 109 −43.403 −54.111 −2.500 1.00 88.63 A N ATOM 847 CD2 HIS A 109 −42.206 −54.297 −1.860 1.00 89.44 A C ATOM 848 C HIS A 109 −39.475 −55.941 −2.821 1.00 92.55 A C ATOM 849 O HIS A 109 −39.790 −56.017 −4.001 1.00 92.58 A O ATOM 850 N ILE A 110 −38.708 −54.969 −2.345 1.00 92.27 A N ATOM 851 CA ILE A 110 −38.276 −53.881 −3.199 1.00 91.90 A C ATOM 852 CB ILE A 110 −37.388 −52.868 −2.466 1.00 91.59 A C ATOM 853 CG1 ILE A 110 −38.168 −52.222 −1.310 1.00 90.96 A C ATOM 854 CD1 ILE A 110 −37.451 −51.090 −0.584 1.00 89.65 A C ATOM 855 CG2 ILE A 110 −36.846 −51.854 −3.465 1.00 90.96 A C ATOM 856 C ILE A 110 −37.533 −54.446 −4.392 1.00 92.23 A C ATOM 857 O ILE A 110 −37.935 −54.231 −5.529 1.00 92.92 A O ATOM 858 N LEU A 111 −36.467 −55.192 −4.136 1.00 92.12 A N ATOM 859 CA LEU A 111 −35.643 −55.697 −5.217 1.00 91.77 A C ATOM 860 CB LEU A 111 −34.491 −56.543 −4.677 1.00 91.73 A C ATOM 861 CG LEU A 111 −33.467 −55.903 −3.741 1.00 90.36 A C ATOM 862 CD1 LEU A 111 −32.463 −56.958 −3.406 1.00 90.12 A C ATOM 863 CD2 LEU A 111 −32.781 −54.692 −4.345 1.00 88.55 A C ATOM 864 C LEU A 111 −36.502 −56.502 −6.169 1.00 91.90 A C ATOM 865 O LEU A 111 −36.383 −56.359 −7.378 1.00 91.88 A O ATOM 866 N GLN A 112 −37.377 −57.333 −5.611 1.00 92.19 A N ATOM 867 CA GLN A 112 −38.380 −58.057 −6.389 1.00 92.61 A C ATOM 868 CB GLN A 112 −39.414 −58.680 −5.441 1.00 92.65 A C ATOM 869 CG GLN A 112 −40.151 −59.873 −5.987 1.00 93.30 A C ATOM 870 CD GLN A 112 −39.304 −61.111 −5.954 1.00 95.39 A C ATOM 871 OE1 GLN A 112 −38.080 −61.029 −5.840 1.00 96.91 A O ATOM 872 NE2 GLN A 112 −39.939 −62.272 −6.046 1.00 95.38 A N ATOM 873 C GLN A 112 −39.073 −57.130 −7.413 1.00 92.52 A C ATOM 874 O GLN A 112 −39.107 −57.420 −8.600 1.00 92.65 A O ATOM 875 N GLN A 113 −39.600 −56.013 −6.930 1.00 92.38 A N ATOM 876 CA GLN A 113 −40.245 −55.004 −7.751 1.00 92.42 A C ATOM 877 CB GLN A 113 −40.604 −53.816 −6.877 1.00 91.83 A C ATOM 878 CG GLN A 113 −41.894 −53.927 −6.140 1.00 87.77 A C ATOM 879 CD GLN A 113 −42.411 −52.578 −5.848 1.00 82.89 A C ATOM 880 OE1 GLN A 113 −41.639 −51.658 −5.644 1.00 82.06 A O ATOM 881 NE2 GLN A 113 −43.713 −52.425 −5.856 1.00 81.92 A N ATOM 882 C GLN A 113 −39.361 −54.474 −8.860 1.00 93.60 A C ATOM 883 O GLN A 113 −39.792 −54.359 −9.999 1.00 93.71 A O ATOM 884 N VAL A 114 −38.136 −54.118 −8.494 1.00 95.00 A N ATOM 885 CA VAL A 114 −37.148 −53.565 −9.417 1.00 96.40 A C ATOM 886 CB VAL A 114 −35.803 −53.293 −8.696 1.00 96.33 A C ATOM 887 CG1 VAL A 114 −34.789 −52.673 −9.645 1.00 96.52 A C ATOM 888 CG2 VAL A 114 −36.021 −52.384 −7.508 1.00 96.64 A C ATOM 889 C VAL A 114 −36.922 −54.495 −10.597 1.00 97.20 A C ATOM 890 O VAL A 114 −36.969 −54.078 −11.742 1.00 97.10 A O ATOM 891 N TYR A 115 −36.677 −55.758 −10.291 1.00 98.86 A N ATOM 892 CA TYR A 115 −36.532 −56.801 −11.287 1.00 100.76 A C ATOM 893 CB TYR A 115 −36.385 −58.127 −10.557 1.00 100.48 A C ATOM 894 CG TYR A 115 −35.930 −59.319 −11.360 1.00 100.03 A C ATOM 895 CD1 TYR A 115 −34.578 −59.555 −11.591 1.00 100.29 A C ATOM 896 CE1 TYR A 115 −34.154 −60.679 −12.290 1.00 99.90 A C ATOM 897 CZ TYR A 115 −35.091 −61.589 −12.745 1.00 99.88 A C ATOM 898 OH TYR A 115 −34.690 −62.708 −13.444 1.00 100.50 A O ATOM 899 CE2 TYR A 115 −36.436 −61.386 −12.504 1.00 99.43 A C ATOM 900 CD2 TYR A 115 −36.844 −60.258 −11.811 1.00 99.36 A C ATOM 901 C TYR A 115 −37.755 −56.813 −12.218 1.00 102.30 A C ATOM 902 O TYR A 115 −37.630 −56.563 −13.424 1.00 102.67 A O ATOM 903 N ASN A 116 −38.935 −57.057 −11.652 1.00 103.84 A N ATOM 904 CA ASN A 116 −40.159 −57.132 −12.437 1.00 105.35 A C ATOM 905 CB ASN A 116 −41.409 −57.186 −11.544 1.00 105.53 A C ATOM 906 CG ASN A 116 −41.299 −58.201 −10.395 1.00 106.42 A C ATOM 907 OD1 ASN A 116 −41.958 −58.039 −9.362 1.00 107.61 A O ATOM 908 ND2 ASN A 116 −40.473 −59.236 −10.563 1.00 105.87 A N ATOM 909 C ASN A 116 −40.259 −55.963 −13.411 1.00 106.26 A C ATOM 910 O ASN A 116 −40.374 −56.166 −14.612 1.00 106.58 A O ATOM 911 N HIS A 117 −40.184 −54.742 −12.899 1.00 107.58 A N ATOM 912 CA HIS A 117 −40.309 −53.569 −13.753 1.00 109.13 A C ATOM 913 CB HIS A 117 −40.525 −52.295 −12.932 1.00 108.80 A C ATOM 914 CG HIS A 117 −41.802 −52.277 −12.155 1.00 108.67 A C ATOM 915 ND1 HIS A 117 −43.040 −52.297 −12.757 1.00 107.97 A N ATOM 916 CE1 HIS A 117 −43.979 −52.264 −11.827 1.00 107.76 A C ATOM 917 NE2 HIS A 117 −43.394 −52.216 −10.645 1.00 107.59 A N ATOM 918 CD2 HIS A 117 −42.033 −52.221 −10.821 1.00 108.97 A C ATOM 919 C HIS A 117 −39.108 −53.374 −14.674 1.00 110.51 A C ATOM 920 O HIS A 117 −39.188 −52.593 −15.617 1.00 110.72 A O ATOM 921 N SER A 118 −38.002 −54.067 −14.412 1.00 112.27 A N ATOM 922 CA SER A 118 −36.784 −53.842 −15.193 1.00 114.20 A C ATOM 923 CB SER A 118 −35.614 −53.463 −14.292 1.00 114.06 A C ATOM 924 OG SER A 118 −35.922 −52.302 −13.543 1.00 113.94 A O ATOM 925 C SER A 118 −36.410 −55.003 −16.100 1.00 115.70 A C ATOM 926 O SER A 118 −36.144 −54.806 −17.286 1.00 115.72 A O ATOM 927 N VAL A 119 −36.383 −56.208 −15.544 1.00 117.78 N ATOM 928 CA VAL A 119 −36.160 −57.408 −16.340 1.00 119.93 C ATOM 929 CB VAL A 119 −35.673 −58.596 −15.477 1.00 119.63 C ATOM 930 CG1 VAL A 119 −35.786 −59.905 −16.231 1.00 119.45 C ATOM 931 CG2 VAL A 119 −34.234 −58.376 −15.052 1.00 119.70 C ATOM 932 C VAL A 119 −37.459 −57.724 −17.065 1.00 121.78 C ATOM 933 O VAL A 119 −38.297 −58.483 −16.566 1.00 122.10 O ATOM 934 N THR A 120 −37.623 −57.105 −18.234 1.00 124.15 N ATOM 935 CA THR A 120 −38.833 −57.259 −19.053 1.00 126.32 C ATOM 936 CB THR A 120 −38.907 −56.229 −20.231 1.00 126.35 C ATOM 937 OG1 THR A 120 −37.839 −56.462 −21.161 1.00 127.01 O ATOM 938 CG2 THR A 120 −38.827 −54.783 −19.725 1.00 126.37 C ATOM 939 C THR A 120 −38.957 −58.675 −19.605 1.00 127.69 C ATOM 940 O THR A 120 −40.058 −59.198 −19.699 1.00 128.05 O ATOM 941 N ASP A 121 −37.830 −59.299 −19.945 1.00 129.56 N ATOM 942 CA ASP A 121 −37.846 −60.622 −20.563 1.00 131.49 C ATOM 943 CB ASP A 121 −37.269 −60.545 −21.982 1.00 131.52 C ATOM 944 CG ASP A 121 −37.878 −61.574 −22.925 1.00 131.55 C ATOM 945 OD1 ASP A 121 −38.153 −62.721 −22.491 1.00 130.99 O ATOM 946 OD2 ASP A 121 −38.068 −61.227 −24.111 1.00 131.26 O ATOM 947 C ASP A 121 −37.104 −61.664 −19.723 1.00 132.90 C ATOM 948 O ASP A 121 −35.930 −61.933 −19.971 1.00 132.87 O ATOM 949 N PRO A 122 −37.801 −62.273 −18.743 1.00 134.59 N ATOM 950 CA PRO A 122 −37.178 −63.129 −17.722 1.00 136.07 C ATOM 951 CB PRO A 122 −38.356 −63.509 −16.815 1.00 135.91 C ATOM 952 CG PRO A 122 −39.542 −63.437 −17.700 1.00 135.41 C ATOM 953 CD PRO A 122 −39.271 −62.272 −18.621 1.00 134.73 C ATOM 954 C PRO A 122 −36.526 −64.390 −18.279 1.00 137.66 C ATOM 955 O PRO A 122 −35.513 −64.845 −17.742 1.00 137.77 O ATOM 956 N GLU A 123 −37.114 −64.941 −19.340 1.00 139.58 N ATOM 957 CA GLU A 123 −36.647 −66.184 −19.943 1.00 141.45 C ATOM 958 CB GLU A 123 −37.787 −66.856 −20.720 1.00 141.28 C ATOM 959 CG GLU A 123 −37.550 −68.326 −21.086 1.00 141.34 C ATOM 960 CD GLU A 123 −37.023 −69.163 −19.927 1.00 141.02 C ATOM 961 OE1 GLU A 123 −35.964 −69.805 −20.088 1.00 140.73 O ATOM 962 OE2 GLU A 123 −37.659 −69.179 −18.856 1.00 141.54 O ATOM 963 C GLU A 123 −35.437 −65.934 −20.841 1.00 142.98 C ATOM 964 O GLU A 123 −34.639 −66.844 −21.088 1.00 143.13 O ATOM 965 N LYS A 124 −35.297 −64.690 −21.299 1.00 144.91 N ATOM 966 CA LYS A 124 −34.191 −64.272 −22.165 1.00 146.91 C ATOM 967 CB LYS A 124 −34.550 −62.953 −22.837 1.00 146.74 C ATOM 968 CG LYS A 124 −35.060 −63.102 −24.255 1.00 146.47 C ATOM 969 CD LYS A 124 −34.116 −62.423 −25.217 1.00 145.90 C ATOM 970 CE LYS A 124 −34.296 −60.917 −25.162 1.00 145.62 C ATOM 971 NZ LYS A 124 −33.048 −60.206 −25.518 1.00 145.62 N ATOM 972 C LYS A 124 −32.822 −64.170 −21.468 1.00 148.55 C ATOM 973 O LYS A 124 −31.928 −63.451 −21.932 1.00 148.68 O ATOM 974 N LEU A 125 −32.671 −64.895 −20.362 1.00 150.70 N ATOM 975 CA LEU A 125 −31.401 −65.007 −19.649 1.00 152.83 C ATOM 976 CB LEU A 125 −31.524 −64.444 −18.226 1.00 152.70 C ATOM 977 CG LEU A 125 −31.804 −62.947 −18.024 1.00 152.49 C ATOM 978 CD1 LEU A 125 −32.110 −62.651 −16.565 1.00 152.28 C ATOM 979 CD2 LEU A 125 −30.650 −62.084 −18.503 1.00 152.11 C ATOM 980 C LEU A 125 −30.937 −66.467 −19.622 1.00 154.52 C ATOM 981 O LEU A 125 −30.066 −66.848 −18.834 1.00 154.82 O ATOM 982 N ASN A 126 −31.550 −67.282 −20.479 1.00 156.62 N ATOM 983 CA ASN A 126 −31.116 −68.658 −20.734 1.00 158.65 C ATOM 984 CB ASN A 126 −31.977 −69.663 −19.957 1.00 158.64 C ATOM 985 CG ASN A 126 −31.550 −69.804 −18.503 1.00 158.89 C ATOM 986 OD1 ASN A 126 −31.014 −70.840 −18.100 1.00 158.95 O ATOM 987 ND2 ASN A 126 −31.789 −68.764 −17.708 1.00 158.90 N ATOM 988 C ASN A 126 −31.138 −68.962 −22.239 1.00 160.04 C ATOM 989 O ASN A 126 −31.161 −70.123 −22.660 1.00 160.17 O ATOM 990 N ASN A 127 −31.134 −67.893 −23.036 1.00 161.88 N ATOM 991 CA ASN A 127 −31.115 −67.972 −24.497 1.00 163.62 C ATOM 992 CB ASN A 127 −32.304 −67.207 −25.093 1.00 163.57 C ATOM 993 CG ASN A 127 −33.318 −68.118 −25.768 1.00 163.96 C ATOM 994 OD1 ASN A 127 −33.038 −69.287 −26.059 1.00 164.21 O ATOM 995 ND2 ASN A 127 −34.504 −67.577 −26.038 1.00 163.90 N ATOM 996 C ASN A 127 −29.820 −67.454 −25.119 1.00 164.83 C ATOM 997 O ASN A 127 −29.559 −67.707 −26.299 1.00 164.96 O ATOM 998 N TYR A 128 −29.025 −66.725 −24.329 1.00 166.43 N ATOM 999 CA TYR A 128 −27.774 −66.111 −24.806 1.00 167.84 C ATOM 1000 CB TYR A 128 −27.170 −65.122 −23.769 1.00 167.86 C ATOM 1001 CG TYR A 128 −27.131 −65.552 −22.298 1.00 167.90 C ATOM 1002 CD1 TYR A 128 −26.892 −66.881 −21.923 1.00 167.91 C ATOM 1003 CE1 TYR A 128 −26.841 −67.262 −20.582 1.00 168.14 C ATOM 1004 CZ TYR A 128 −27.010 −66.309 −19.594 1.00 168.45 C ATOM 1005 OH TYR A 128 −26.957 −66.686 −18.268 1.00 168.38 O ATOM 1006 CE2 TYR A 128 −27.235 −64.979 −19.935 1.00 168.53 C ATOM 1007 CD2 TYR A 128 −27.286 −64.608 −21.282 1.00 167.98 C ATOM 1008 C TYR A 128 −26.750 −67.158 −25.265 1.00 168.74 C ATOM 1009 O TYR A 128 −26.914 −67.784 −26.315 1.00 168.84 O ATOM 1010 N GLU A 129 −25.687 −67.322 −24.489 1.00 169.93 N ATOM 1011 CA GLU A 129 −24.806 −68.468 −24.627 1.00 171.09 C ATOM 1012 CB GLU A 129 −23.470 −68.049 −25.254 1.00 171.03 C ATOM 1013 CG GLU A 129 −23.566 −67.808 −26.768 1.00 171.17 C ATOM 1014 CD GLU A 129 −22.213 −67.721 −27.464 1.00 171.32 C ATOM 1015 OE1 GLU A 129 −21.966 −68.548 −28.370 1.00 171.27 O ATOM 1016 OE2 GLU A 129 −21.402 −66.831 −27.118 1.00 171.14 O ATOM 1017 C GLU A 129 −24.660 −69.124 −23.240 1.00 171.92 C ATOM 1018 O GLU A 129 −23.680 −68.863 −22.531 1.00 172.00 O ATOM 1019 N PRO A 130 −25.660 −69.957 −22.840 1.00 172.71 N ATOM 1020 CA PRO A 130 −25.750 −70.540 −21.491 1.00 173.17 C ATOM 1021 CB PRO A 130 −27.222 −70.985 −21.381 1.00 173.16 C ATOM 1022 CG PRO A 130 −27.883 −70.567 −22.679 1.00 173.07 C ATOM 1023 CD PRO A 130 −26.785 −70.409 −23.679 1.00 172.78 C ATOM 1024 C PRO A 130 −24.792 −71.718 −21.300 1.00 173.69 C ATOM 1025 O PRO A 130 −25.213 −72.887 −21.242 1.00 173.66 O ATOM 1026 N PHE A 131 −23.506 −71.366 −21.206 1.00 174.28 N ATOM 1027 CA PHE A 131 −22.381 −72.287 −21.015 1.00 174.71 C ATOM 1028 CB PHE A 131 −22.248 −73.261 −22.206 1.00 174.70 C ATOM 1029 CG PHE A 131 −21.764 −74.649 −21.834 1.00 174.86 C ATOM 1030 CD1 PHE A 131 −22.304 −75.336 −20.744 1.00 174.99 C ATOM 1031 CE1 PHE A 131 −21.858 −76.617 −20.417 1.00 174.83 C ATOM 1032 CZ PHE A 131 −20.879 −77.229 −21.195 1.00 174.69 C ATOM 1033 CE2 PHE A 131 −20.341 −76.562 −22.287 1.00 174.58 C ATOM 1034 CD2 PHE A 131 −20.793 −75.287 −22.608 1.00 174.75 C ATOM 1035 C PHE A 131 −21.119 −71.416 −20.832 1.00 174.86 C ATOM 1036 O PHE A 131 −20.247 −71.743 −20.023 1.00 175.08 O ATOM 1037 N SER A 132 −21.061 −70.294 −21.558 1.00 174.97 N ATOM 1038 CA SER A 132 −19.960 −69.310 −21.489 1.00 175.00 C ATOM 1039 CB SER A 132 −19.937 −68.461 −22.772 1.00 174.99 C ATOM 1040 OG SER A 132 −19.127 −67.304 −22.638 1.00 174.53 O ATOM 1041 C SER A 132 −20.034 −68.385 −20.255 1.00 175.05 C ATOM 1042 O SER A 132 −21.132 −67.979 −19.852 1.00 174.99 O ATOM 1043 N PRO A 133 −18.863 −68.047 −19.659 1.00 175.04 N ATOM 1044 CA PRO A 133 −18.789 −67.099 −18.536 1.00 175.00 C ATOM 1045 CB PRO A 133 −17.290 −67.060 −18.211 1.00 174.97 C ATOM 1046 CG PRO A 133 −16.776 −68.373 −18.673 1.00 175.04 C ATOM 1047 CD PRO A 133 −17.548 −68.660 −19.930 1.00 175.02 C ATOM 1048 C PRO A 133 −19.277 −65.695 −18.902 1.00 174.94 C ATOM 1049 O PRO A 133 −20.354 −65.277 −18.465 1.00 174.78 O ATOM 1050 N GLU A 138 −29.909 −69.344 −11.491 1.00 122.62 N ATOM 1051 CA GLU A 138 −30.959 −69.003 −10.522 1.00 122.35 C ATOM 1052 CB GLU A 138 −32.087 −70.054 −10.528 1.00 122.42 C ATOM 1053 CG GLU A 138 −33.396 −69.606 −9.847 1.00 122.39 C ATOM 1054 CD GLU A 138 −33.888 −68.247 −10.321 1.00 122.02 C ATOM 1055 OE1 GLU A 138 −33.217 −67.228 −10.045 1.00 121.61 O ATOM 1056 OE2 GLU A 138 −34.955 −68.197 −10.964 1.00 122.23 O ATOM 1057 C GLU A 138 −30.424 −68.752 −9.098 1.00 121.95 C ATOM 1058 O GLU A 138 −29.910 −69.663 −8.432 1.00 121.97 O ATOM 1059 N THR A 139 −30.569 −67.503 −8.654 1.00 121.28 A N ATOM 1060 CA THR A 139 −29.998 −67.012 −7.393 1.00 120.63 A C ATOM 1061 CB THR A 139 −28.869 −65.948 −7.657 1.00 120.86 A C ATOM 1062 OG1 THR A 139 −27.709 −66.586 −8.219 1.00 121.04 A O ATOM 1063 CG2 THR A 139 −28.463 −65.223 −6.371 1.00 121.28 A C ATOM 1064 C THR A 139 −31.088 −66.414 −6.493 1.00 119.61 A C ATOM 1065 O THR A 139 −32.022 −65.767 −6.977 1.00 119.72 A O ATOM 1066 N SER A 140 −30.965 −66.629 −5.186 1.00 118.16 A N ATOM 1067 CA SER A 140 −31.941 −66.087 −4.255 1.00 116.53 A C ATOM 1068 CB SER A 140 −32.513 −67.165 −3.342 1.00 116.83 A C ATOM 1069 OG SER A 140 −33.619 −66.633 −2.637 1.00 117.73 A O ATOM 1070 C SER A 140 −31.398 −64.956 −3.418 1.00 115.04 A C ATOM 1071 O SER A 140 −30.184 −64.747 −3.326 1.00 114.61 A O ATOM 1072 N PHE A 141 −32.341 −64.232 −2.825 1.00 113.32 A N ATOM 1073 CA PHE A 141 −32.081 −63.082 −1.976 1.00 111.77 A C ATOM 1074 CB PHE A 141 −33.333 −62.202 −1.952 1.00 111.32 A C ATOM 1075 CG PHE A 141 −33.353 −61.197 −0.857 1.00 109.82 A C ATOM 1076 CD1 PHE A 141 −32.867 −59.922 −1.067 1.00 108.92 A C ATOM 1077 CE1 PHE A 141 −32.887 −58.980 −0.051 1.00 108.69 A C ATOM 1078 CZ PHE A 141 −33.409 −59.311 1.193 1.00 108.97 A C ATOM 1079 CE2 PHE A 141 −33.908 −60.580 1.414 1.00 109.04 A C ATOM 1080 CD2 PHE A 141 −33.882 −61.516 0.385 1.00 109.44 A C ATOM 1081 C PHE A 141 −31.727 −63.579 −0.580 1.00 111.19 A C ATOM 1082 O PHE A 141 −30.793 −63.083 0.056 1.00 110.99 A O ATOM 1083 N ASP A 142 −32.488 −64.568 −0.120 1.00 110.29 A N ATOM 1084 CA ASP A 142 −32.258 −65.219 1.157 1.00 109.27 A C ATOM 1085 CB ASP A 142 −33.087 −66.500 1.247 1.00 109.11 A C ATOM 1086 CG ASP A 142 −34.535 −66.289 0.833 1.00 108.30 A C ATOM 1087 OD1 ASP A 142 −35.038 −65.152 0.964 1.00 107.42 A O ATOM 1088 OD2 ASP A 142 −35.167 −67.262 0.372 1.00 107.28 A O ATOM 1089 C ASP A 142 −30.781 −65.529 1.311 1.00 108.81 A C ATOM 1090 O ASP A 142 −30.120 −64.967 2.183 1.00 109.14 A O ATOM 1091 N LEU A 143 −30.265 −66.392 0.437 1.00 107.87 A N ATOM 1092 CA LEU A 143 −28.848 −66.771 0.440 1.00 106.92 A C ATOM 1093 CB LEU A 143 −28.483 −67.450 −0.883 1.00 106.94 A C ATOM 1094 CG LEU A 143 −27.239 −68.336 −0.972 1.00 106.72 A C ATOM 1095 CD1 LEU A 143 −27.518 −69.493 −1.900 1.00 107.28 A C ATOM 1096 CD2 LEU A 143 −26.021 −67.576 −1.452 1.00 106.57 A C ATOM 1097 C LEU A 143 −27.941 −65.576 0.680 1.00 106.27 A C ATOM 1098 O LEU A 143 −27.200 −65.550 1.646 1.00 106.11 A O ATOM 1099 N VAL A 144 −28.031 −64.586 −0.198 1.00 105.85 A N ATOM 1100 CA VAL A 144 −27.158 −63.419 −0.163 1.00 105.76 A C ATOM 1101 CB VAL A 144 −27.533 −62.401 −1.262 1.00 105.92 A C ATOM 1102 CG1 VAL A 144 −26.543 −61.238 −1.290 1.00 105.32 A C ATOM 1103 CG2 VAL A 144 −27.600 −63.085 −2.624 1.00 106.23 A C ATOM 1104 C VAL A 144 −27.207 −62.733 1.191 1.00 105.69 A C ATOM 1105 O VAL A 144 −26.166 −62.436 1.774 1.00 105.77 A O ATOM 1106 N ALA A 145 −28.423 −62.493 1.684 1.00 105.53 A N ATOM 1107 CA ALA A 145 −28.627 −61.930 3.013 1.00 104.91 A C ATOM 1108 CB ALA A 145 −30.070 −62.066 3.439 1.00 104.87 A C ATOM 1109 C ALA A 145 −27.720 −62.646 3.988 1.00 104.65 A C ATOM 1110 O ALA A 145 −26.987 −62.000 4.721 1.00 104.81 A O ATOM 1111 N GLN A 146 −27.738 −63.978 3.965 1.00 104.22 A N ATOM 1112 CA GLN A 146 −26.919 −64.759 4.876 1.00 103.95 A C ATOM 1113 CB GLN A 146 −27.111 −66.251 4.658 1.00 103.98 A C ATOM 1114 CG GLN A 146 −26.538 −67.077 5.793 1.00 104.95 A C ATOM 1115 CD GLN A 146 −26.068 −68.461 5.367 1.00 106.24 A C ATOM 1116 OE1 GLN A 146 −25.018 −68.931 5.823 1.00 105.97 A O ATOM 1117 NE2 GLN A 146 −26.838 −69.123 4.493 1.00 106.07 A N ATOM 1118 C GLN A 146 −25.456 −64.411 4.729 1.00 103.76 A C ATOM 1119 O GLN A 146 −24.802 −64.069 5.704 1.00 104.00 A O ATOM 1120 N MET A 147 −24.954 −64.471 3.501 1.00 103.72 A N ATOM 1121 CA MET A 147 −23.542 −64.220 3.223 1.00 103.38 A C ATOM 1122 CB MET A 147 −23.209 −64.601 1.786 1.00 102.77 A C ATOM 1123 CG MET A 147 −23.824 −65.898 1.341 1.00 101.47 A C ATOM 1124 SD MET A 147 −23.047 −67.340 2.084 1.00 100.07 A S ATOM 1125 CE MET A 147 −24.302 −68.599 1.868 1.00 98.57 A C ATOM 1126 C MET A 147 −23.195 −62.762 3.477 1.00 103.90 A C ATOM 1127 O MET A 147 −22.086 −62.329 3.214 1.00 103.84 A O ATOM 1128 N ILE A 148 −24.166 −62.008 3.973 1.00 104.56 A N ATOM 1129 CA ILE A 148 −23.946 −60.638 4.389 1.00 105.39 A C ATOM 1130 CB ILE A 148 −25.110 −59.733 3.944 1.00 105.31 A C ATOM 1131 CG1 ILE A 148 −24.993 −59.418 2.455 1.00 104.87 A C ATOM 1132 CD1 ILE A 148 −26.317 −59.129 1.812 1.00 105.02 A C ATOM 1133 CG2 ILE A 148 −25.179 −58.450 4.782 1.00 104.85 A C ATOM 1134 C ILE A 148 −23.841 −60.624 5.902 1.00 106.30 A C ATOM 1135 O ILE A 148 −23.096 −59.819 6.473 1.00 106.42 A O ATOM 1136 N ASP A 149 −24.593 −61.524 6.537 1.00 107.27 A N ATOM 1137 CA ASP A 149 −24.664 −61.604 7.988 1.00 108.31 A C ATOM 1138 CB ASP A 149 −25.669 −62.666 8.418 1.00 108.25 A C ATOM 1139 CG ASP A 149 −27.095 −62.283 8.103 1.00 109.02 A C ATOM 1140 OD1 ASP A 149 −27.366 −61.070 7.944 1.00 110.17 A O ATOM 1141 OD2 ASP A 149 −27.953 −63.196 8.023 1.00 109.04 A O ATOM 1142 C ASP A 149 −23.302 −61.926 8.558 1.00 109.13 A C ATOM 1143 O ASP A 149 −22.696 −61.094 9.227 1.00 109.38 A O ATOM 1144 N GLU A 150 −22.811 −63.126 8.272 1.00 110.18 A N ATOM 1145 CA GLU A 150 −21.523 −63.552 8.796 1.00 111.36 A C ATOM 1146 CB GLU A 150 −21.227 −65.003 8.437 1.00 111.58 A C ATOM 1147 CG GLU A 150 −22.168 −65.999 9.074 1.00 113.22 A C ATOM 1148 CD GLU A 150 −22.105 −67.345 8.388 1.00 115.56 A C ATOM 1149 OE1 GLU A 150 −21.987 −67.353 7.139 1.00 116.52 A O ATOM 1150 OE2 GLU A 150 −22.168 −68.384 9.091 1.00 115.98 A O ATOM 1151 C GLU A 150 −20.415 −62.640 8.291 1.00 111.65 A C ATOM 1152 O GLU A 150 −19.692 −62.056 9.094 1.00 112.09 A O ATOM 1153 N ILE A 151 −20.300 −62.499 6.970 1.00 111.73 A N ATOM 1154 CA ILE A 151 −19.300 −61.621 6.367 1.00 111.70 A C ATOM 1155 CB ILE A 151 −19.724 −61.186 4.944 1.00 111.67 A C ATOM 1156 CG1 ILE A 151 −19.205 −62.196 3.923 1.00 111.68 A C ATOM 1157 CD1 ILE A 151 −17.729 −62.111 3.647 1.00 112.17 A C ATOM 1158 CG2 ILE A 151 −19.247 −59.773 4.593 1.00 111.38 A C ATOM 1159 C ILE A 151 −18.991 −60.417 7.254 1.00 111.89 A C ATOM 1160 O ILE A 151 −17.823 −60.047 7.430 1.00 111.96 A O ATOM 1161 N LYS A 152 −20.042 −59.840 7.831 1.00 111.95 A N ATOM 1162 CA LYS A 152 −19.924 −58.696 8.718 1.00 112.37 A C ATOM 1163 CB LYS A 152 −19.314 −59.121 10.062 1.00 112.43 A C ATOM 1164 CG LYS A 152 −19.600 −58.167 11.223 1.00 113.91 A C ATOM 1165 CD LYS A 152 −18.364 −57.331 11.600 1.00 115.98 A C ATOM 1166 CE LYS A 152 −18.348 −55.950 10.945 1.00 116.28 A C ATOM 1167 NZ LYS A 152 −19.371 −55.033 11.524 1.00 117.21 A N ATOM 1168 C LYS A 152 −19.133 −57.569 8.044 1.00 112.21 A C ATOM 1169 O LYS A 152 −17.934 −57.687 7.794 1.00 112.05 A O ATOM 1170 N MET A 153 −19.816 −56.474 7.745 1.00 112.28 A N ATOM 1171 CA MET A 153 −19.178 −55.393 7.024 1.00 112.54 A C ATOM 1172 CB MET A 153 −19.952 −55.044 5.760 1.00 112.47 A C ATOM 1173 CG MET A 153 −19.949 −56.139 4.734 1.00 112.04 A C ATOM 1174 SD MET A 153 −19.755 −55.436 3.109 1.00 111.27 A S ATOM 1175 CE MET A 153 −20.314 −56.816 2.136 1.00 111.40 A C ATOM 1176 C MET A 153 −19.025 −54.163 7.873 1.00 112.84 A C ATOM 1177 O MET A 153 −20.005 −53.474 8.160 1.00 113.02 A O ATOM 1178 N THR A 154 −17.784 −53.892 8.267 1.00 113.08 A N ATOM 1179 CA THR A 154 −17.438 −52.658 8.955 1.00 113.22 A C ATOM 1180 CB THR A 154 −15.972 −52.664 9.421 1.00 113.33 A C ATOM 1181 OG1 THR A 154 −15.102 −52.391 8.311 1.00 113.58 A O ATOM 1182 CG2 THR A 154 −15.605 −54.012 10.038 1.00 113.35 A C ATOM 1183 C THR A 154 −17.634 −51.511 7.982 1.00 113.29 A C ATOM 1184 O THR A 154 −17.495 −51.692 6.768 1.00 113.25 A O ATOM 1185 N ASP A 155 −17.946 −50.333 8.508 1.00 113.44 A N ATOM 1186 CA ASP A 155 −18.173 −49.157 7.657 1.00 113.63 A C ATOM 1187 CB ASP A 155 −18.685 −47.946 8.473 1.00 113.84 A C ATOM 1188 CG ASP A 155 −18.525 −48.123 9.985 1.00 113.84 A C ATOM 1189 OD1 ASP A 155 −19.249 −48.960 10.569 1.00 113.56 A O ATOM 1190 OD2 ASP A 155 −17.698 −47.398 10.585 1.00 113.72 A O ATOM 1191 C ASP A 155 −16.962 −48.780 6.781 1.00 113.43 A C ATOM 1192 O ASP A 155 −16.954 −47.730 6.126 1.00 113.49 A O ATOM 1193 N ASP A 156 −15.960 −49.654 6.760 1.00 113.13 A N ATOM 1194 CA ASP A 156 −14.741 −49.429 5.992 1.00 113.04 A C ATOM 1195 CB ASP A 156 −13.518 −49.876 6.799 1.00 113.50 A C ATOM 1196 CG ASP A 156 −13.350 −49.089 8.098 1.00 115.24 A C ATOM 1197 OD1 ASP A 156 −12.995 −47.881 8.025 1.00 116.26 A O ATOM 1198 OD2 ASP A 156 −13.564 −49.687 9.188 1.00 116.50 A O ATOM 1199 C ASP A 156 −14.761 −50.141 4.637 1.00 112.37 A C ATOM 1200 O ASP A 156 −14.457 −49.521 3.598 1.00 112.39 A O ATOM 1201 N ASP A 157 −15.138 −51.428 4.661 1.00 111.11 A N ATOM 1202 CA ASP A 157 −15.032 −52.352 3.511 1.00 109.57 A C ATOM 1203 CB ASP A 157 −15.718 −53.683 3.837 1.00 109.55 A C ATOM 1204 CG ASP A 157 −15.232 −54.287 5.131 1.00 109.55 A C ATOM 1205 OD1 ASP A 157 −14.007 −54.299 5.353 1.00 110.05 A O ATOM 1206 OD2 ASP A 157 −16.074 −54.755 5.926 1.00 109.20 A O ATOM 1207 C ASP A 157 −15.578 −51.824 2.177 1.00 108.49 A C ATOM 1208 O ASP A 157 −16.474 −50.965 2.153 1.00 108.32 A O ATOM 1209 N LEU A 158 −15.018 −52.346 1.080 1.00 106.93 A N ATOM 1210 CA LEU A 158 −15.535 −52.120 −0.278 1.00 105.21 A C ATOM 1211 CB LEU A 158 −14.510 −51.420 −1.162 1.00 105.22 A C ATOM 1212 CG LEU A 158 −14.669 −49.922 −1.397 1.00 104.64 A C ATOM 1213 CD1 LEU A 158 −14.210 −49.144 −0.179 1.00 104.82 A C ATOM 1214 CD2 LEU A 158 −13.855 −49.536 −2.611 1.00 104.32 A C ATOM 1215 C LEU A 158 −15.949 −53.425 −0.937 1.00 104.15 A C ATOM 1216 O LEU A 158 −15.259 −54.446 −0.800 1.00 103.80 A O ATOM 1217 N PHE A 159 −17.073 −53.369 −1.657 1.00 102.77 A N ATOM 1218 CA PHE A 159 −17.702 −54.549 −2.248 1.00 101.04 A C ATOM 1219 CB PHE A 159 −19.193 −54.553 −1.927 1.00 101.03 A C ATOM 1220 CG PHE A 159 −19.898 −55.809 −2.336 1.00 100.64 A C ATOM 1221 CD1 PHE A 159 −20.085 −56.835 −1.429 1.00 100.74 A C ATOM 1222 CE1 PHE A 159 −20.743 −58.009 −1.799 1.00 100.39 A C ATOM 1223 CZ PHE A 159 −21.213 −58.161 −3.089 1.00 100.62 A C ATOM 1224 CE2 PHE A 159 −21.034 −57.137 −4.008 1.00 101.11 A C ATOM 1225 CD2 PHE A 159 −20.384 −55.966 −3.625 1.00 101.01 A C ATOM 1226 C PHE A 159 −17.529 −54.554 −3.747 1.00 99.89 A C ATOM 1227 O PHE A 159 −17.535 −53.494 −4.372 1.00 99.93 A O ATOM 1228 N VAL A 160 −17.379 −55.752 −4.310 1.00 98.31 A N ATOM 1229 CA VAL A 160 −17.427 −55.959 −5.758 1.00 96.89 A C ATOM 1230 CB VAL A 160 −16.051 −55.744 −6.425 1.00 96.76 A C ATOM 1231 CG1 VAL A 160 −15.769 −56.808 −7.421 1.00 97.04 A C ATOM 1232 CG2 VAL A 160 −15.990 −54.408 −7.102 1.00 96.85 A C ATOM 1233 C VAL A 160 −18.004 −57.323 −6.133 1.00 96.03 A C ATOM 1234 O VAL A 160 −17.438 −58.373 −5.814 1.00 95.68 A O ATOM 1235 N ASP A 161 −19.154 −57.297 −6.796 1.00 95.18 A N ATOM 1236 CA ASP A 161 −19.655 −58.472 −7.489 1.00 94.25 A C ATOM 1237 CB ASP A 161 −21.134 −58.335 −7.789 1.00 93.70 A C ATOM 1238 CG ASP A 161 −21.758 −59.651 −8.166 1.00 93.95 A C ATOM 1239 OD1 ASP A 161 −20.989 −60.600 −8.470 1.00 93.40 A O ATOM 1240 OD2 ASP A 161 −23.013 −59.749 −8.143 1.00 93.73 A O ATOM 1241 C ASP A 161 −18.868 −58.710 −8.793 1.00 94.03 A C ATOM 1242 O ASP A 161 −18.755 −57.843 −9.662 1.00 94.26 A O ATOM 1243 N LEU A 162 −18.295 −59.892 −8.914 1.00 93.43 A N ATOM 1244 CA LEU A 162 −17.558 −60.233 −10.106 1.00 92.67 A C ATOM 1245 CB LEU A 162 −16.258 −60.959 −9.755 1.00 92.01 A C ATOM 1246 CG LEU A 162 −15.128 −60.147 −9.126 1.00 90.25 A C ATOM 1247 CD1 LEU A 162 −13.916 −61.024 −8.999 1.00 89.47 A C ATOM 1248 CD2 LEU A 162 −14.790 −58.927 −9.923 1.00 88.14 A C ATOM 1249 C LEU A 162 −18.465 −61.097 −10.986 1.00 92.95 A C ATOM 1250 O LEU A 162 −18.862 −62.215 −10.598 1.00 93.15 A O ATOM 1251 N GLY A 163 −18.798 −60.566 −12.164 1.00 92.36 A N ATOM 1252 CA GLY A 163 −19.824 −61.172 −12.992 1.00 91.64 A C ATOM 1253 C GLY A 163 −21.166 −60.668 −12.512 1.00 90.99 A C ATOM 1254 O GLY A 163 −22.100 −61.451 −12.250 1.00 90.87 A O ATOM 1255 N SER A 164 −21.242 −59.345 −12.410 1.00 90.03 A N ATOM 1256 CA SER A 164 −22.336 −58.651 −11.755 1.00 89.75 A C ATOM 1257 CB SER A 164 −22.037 −57.149 −11.728 1.00 89.72 A C ATOM 1258 OG SER A 164 −23.203 −56.352 −11.702 1.00 89.77 A O ATOM 1259 C SER A 164 −23.744 −58.925 −12.291 1.00 89.68 A C ATOM 1260 O SER A 164 −24.703 −58.886 −11.519 1.00 89.75 A O ATOM 1261 N GLY A 165 −23.865 −59.195 −13.594 1.00 89.66 A N ATOM 1262 CA GLY A 165 −25.167 −59.400 −14.251 1.00 89.34 A C ATOM 1263 C GLY A 165 −26.010 −58.137 −14.258 1.00 89.44 A C ATOM 1264 O GLY A 165 −25.505 −57.029 −14.458 1.00 89.26 A O ATOM 1265 N VAL A 166 −27.306 −58.301 −14.027 1.00 89.52 A N ATOM 1266 CA VAL A 166 −28.186 −57.155 −13.844 1.00 89.54 A C ATOM 1267 CB VAL A 166 −29.652 −57.540 −13.915 1.00 89.66 A C ATOM 1268 CG1 VAL A 166 −30.143 −57.404 −15.347 1.00 90.17 A C ATOM 1269 CG2 VAL A 166 −29.867 −58.961 −13.379 1.00 90.05 A C ATOM 1270 C VAL A 166 −27.903 −56.473 −12.524 1.00 89.50 A C ATOM 1271 O VAL A 166 −28.244 −55.297 −12.353 1.00 89.71 A O ATOM 1272 N GLY A 167 −27.293 −57.227 −11.602 1.00 89.39 A N ATOM 1273 CA GLY A 167 −26.671 −56.686 −10.387 1.00 88.93 A C ATOM 1274 C GLY A 167 −27.615 −56.436 −9.238 1.00 88.64 A C ATOM 1275 O GLY A 167 −27.595 −55.366 −8.638 1.00 88.15 A O ATOM 1276 N GLN A 168 −28.446 −57.435 −8.947 1.00 88.78 A N ATOM 1277 CA GLN A 168 −29.392 −57.384 −7.829 1.00 88.88 A C ATOM 1278 CB GLN A 168 −30.480 −58.460 −7.959 1.00 88.65 A C ATOM 1279 CG GLN A 168 −30.000 −59.896 −8.038 1.00 88.34 A C ATOM 1280 CD GLN A 168 −29.562 −60.314 −9.432 1.00 89.15 A C ATOM 1281 OE1 GLN A 168 −28.919 −59.551 −10.155 1.00 89.95 A O ATOM 1282 NE2 GLN A 168 −29.886 −61.544 −9.806 1.00 89.52 A N ATOM 1283 C GLN A 168 −28.687 −57.467 −6.477 1.00 88.97 A C ATOM 1284 O GLN A 168 −29.134 −56.870 −5.499 1.00 89.12 A O ATOM 1285 N VAL A 169 −27.570 −58.181 −6.439 1.00 89.02 A N ATOM 1286 CA VAL A 169 −26.742 −58.216 −5.247 1.00 89.32 A C ATOM 1287 CB VAL A 169 −25.693 −59.314 −5.329 1.00 89.26 A C ATOM 1288 CG1 VAL A 169 −24.692 −59.173 −4.199 1.00 88.94 A C ATOM 1289 CG2 VAL A 169 −26.376 −60.676 −5.277 1.00 89.18 A C ATOM 1290 C VAL A 169 −26.111 −56.862 −4.928 1.00 89.64 A C ATOM 1291 O VAL A 169 −26.336 −56.319 −3.857 1.00 89.90 A O ATOM 1292 N VAL A 170 −25.350 −56.301 −5.859 1.00 90.19 A N ATOM 1293 CA VAL A 170 −24.801 −54.947 −5.696 1.00 90.63 A C ATOM 1294 CB VAL A 170 −24.475 −54.295 −7.047 1.00 90.31 A C ATOM 1295 CG1 VAL A 170 −23.230 −53.452 −6.927 1.00 90.60 A C ATOM 1296 CG2 VAL A 170 −24.298 −55.333 −8.107 1.00 90.38 A C ATOM 1297 C VAL A 170 −25.829 −54.047 −5.031 1.00 91.10 A C ATOM 1298 O VAL A 170 −25.522 −53.219 −4.177 1.00 90.88 A O ATOM 1299 N LEU A 171 −27.067 −54.218 −5.442 1.00 92.06 A N ATOM 1300 CA LEU A 171 −28.100 −53.381 −4.939 1.00 93.36 A C ATOM 1301 CB LEU A 171 −29.353 −53.516 −5.804 1.00 93.25 A C ATOM 1302 CG LEU A 171 −29.367 −52.773 −7.138 1.00 92.41 A C ATOM 1303 CD1 LEU A 171 −30.755 −52.865 −7.705 1.00 92.69 A C ATOM 1304 CD2 LEU A 171 −28.956 −51.318 −6.992 1.00 90.99 A C ATOM 1305 C LEU A 171 −28.363 −53.764 −3.494 1.00 94.42 A C ATOM 1306 O LEU A 171 −28.341 −52.909 −2.598 1.00 94.55 A O ATOM 1307 N GLN A 172 −28.590 −55.055 −3.277 1.00 95.39 A N ATOM 1308 CA GLN A 172 −28.908 −55.561 −1.960 1.00 96.41 A C ATOM 1309 CB GLN A 172 −29.049 −57.067 −2.007 1.00 95.92 A C ATOM 1310 CG GLN A 172 −29.323 −57.649 −0.662 1.00 96.66 A C ATOM 1311 CD GLN A 172 −29.583 −59.119 −0.713 1.00 97.85 A C ATOM 1312 OE1 GLN A 172 −29.656 −59.707 −1.797 1.00 99.40 A O ATOM 1313 NE2 GLN A 172 −29.737 −59.736 0.460 1.00 97.11 A N ATOM 1314 C GLN A 172 −27.839 −55.155 −0.945 1.00 97.40 A C ATOM 1315 O GLN A 172 −28.157 −54.701 0.157 1.00 98.00 A O ATOM 1316 N VAL A 173 −26.578 −55.295 −1.336 1.00 98.25 A N ATOM 1317 CA VAL A 173 −25.457 −54.975 −0.475 1.00 99.24 A C ATOM 1318 CB VAL A 173 −24.141 −55.445 −1.105 1.00 99.10 A C ATOM 1319 CG1 VAL A 173 −22.951 −55.016 −0.281 1.00 99.19 A C ATOM 1320 CG2 VAL A 173 −24.158 −56.945 −1.236 1.00 98.87 A C ATOM 1321 C VAL A 173 −25.419 −53.491 −0.130 1.00 100.37 A C ATOM 1322 O VAL A 173 −25.061 −53.119 0.984 1.00 100.55 A O ATOM 1323 N ALA A 174 −25.811 −52.639 −1.071 1.00 101.89 A N ATOM 1324 CA ALA A 174 −25.938 −51.208 −0.775 1.00 103.35 A C ATOM 1325 CB ALA A 174 −26.325 −50.428 −2.032 1.00 103.04 A C ATOM 1326 C ALA A 174 −26.957 −50.974 0.348 1.00 104.32 A C ATOM 1327 O ALA A 174 −26.767 −50.134 1.225 1.00 104.29 A O ATOM 1328 N ALA A 175 −28.021 −51.759 0.326 1.00 105.84 A N ATOM 1329 CA ALA A 175 −29.140 −51.555 1.215 1.00 107.44 A C ATOM 1330 CB ALA A 175 −30.410 −52.069 0.561 1.00 107.37 A C ATOM 1331 C ALA A 175 −28.944 −52.209 2.576 1.00 108.63 A C ATOM 1332 O ALA A 175 −29.691 −51.925 3.521 1.00 109.14 A O ATOM 1333 N ALA A 176 −27.958 −53.092 2.683 1.00 109.75 A N ATOM 1334 CA ALA A 176 −27.764 −53.832 3.925 1.00 110.82 A C ATOM 1335 CB ALA A 176 −27.731 −55.320 3.646 1.00 110.63 A C ATOM 1336 C ALA A 176 −26.513 −53.385 4.681 1.00 111.70 A C ATOM 1337 O ALA A 176 −26.455 −53.462 5.908 1.00 111.87 A O ATOM 1338 N THR A 177 −25.533 −52.893 3.935 1.00 112.83 A N ATOM 1339 CA THR A 177 −24.221 −52.581 4.466 1.00 114.01 A C ATOM 1340 CB THR A 177 −23.171 −53.374 3.725 1.00 113.89 A C ATOM 1341 OG1 THR A 177 −23.074 −52.872 2.383 1.00 113.58 A O ATOM 1342 CG2 THR A 177 −23.537 −54.861 3.702 1.00 113.55 A C ATOM 1343 C THR A 177 −23.904 −51.115 4.235 1.00 115.31 A C ATOM 1344 O THR A 177 −24.268 −50.550 3.201 1.00 115.83 A O ATOM 1345 N ASN A 178 −23.200 −50.497 5.173 1.00 116.62 A N ATOM 1346 CA ASN A 178 −22.938 −49.065 5.065 1.00 117.94 A C ATOM 1347 CB ASN A 178 −23.345 −48.314 6.354 1.00 118.42 A C ATOM 1348 CG ASN A 178 −22.546 −48.749 7.586 1.00 119.90 A C ATOM 1349 OD1 ASN A 178 −21.735 −47.973 8.109 1.00 121.25 A O ATOM 1350 ND2 ASN A 178 −22.776 −49.984 8.057 1.00 120.57 A N ATOM 1351 C ASN A 178 −21.516 −48.727 4.637 1.00 118.23 A C ATOM 1352 O ASN A 178 −20.571 −48.853 5.422 1.00 118.38 A O ATOM 1353 N CYS A 179 −21.367 −48.307 3.382 1.00 118.67 A N ATOM 1354 CA CYS A 179 −20.056 −47.893 2.871 1.00 119.18 A C ATOM 1355 CB CYS A 179 −19.221 −49.113 2.484 1.00 119.20 A C ATOM 1356 SG CYS A 179 −19.810 −50.646 3.221 1.00 120.25 A S ATOM 1357 C CYS A 179 −20.145 −46.935 1.688 1.00 119.12 A C ATOM 1358 O CYS A 179 −21.235 −46.548 1.260 1.00 118.98 A O ATOM 1359 N LYS A 180 −18.981 −46.548 1.176 1.00 119.12 A N ATOM 1360 CA LYS A 180 −18.923 −45.749 −0.034 1.00 119.11 A C ATOM 1361 CB LYS A 180 −17.622 −44.932 −0.121 1.00 119.54 A C ATOM 1362 CG LYS A 180 −17.378 −43.953 1.035 1.00 120.14 A C ATOM 1363 CD LYS A 180 −16.267 −44.463 1.977 1.00 120.95 A C ATOM 1364 CE LYS A 180 −16.407 −43.901 3.399 1.00 121.10 A C ATOM 1365 NZ LYS A 180 −16.393 −42.407 3.477 1.00 120.94 A N ATOM 1366 C LYS A 180 −19.052 −46.691 −1.220 1.00 118.65 A C ATOM 1367 O LYS A 180 −19.071 −47.906 −1.046 1.00 118.49 A O ATOM 1368 N HIS A 181 −19.144 −46.107 −2.411 1.00 118.21 A N ATOM 1369 CA HIS A 181 −19.338 −46.817 −3.676 1.00 118.03 A C ATOM 1370 CB HIS A 181 −18.523 −46.147 −4.784 1.00 118.24 A C ATOM 1371 CG HIS A 181 −19.316 −45.196 −5.615 1.00 118.88 A C ATOM 1372 ND1 HIS A 181 −19.200 −43.828 −5.495 1.00 120.41 A N ATOM 1373 CE1 HIS A 181 −20.029 −43.242 −6.340 1.00 120.88 A C ATOM 1374 NE2 HIS A 181 −20.682 −44.183 −6.999 1.00 121.22 A N ATOM 1375 CD2 HIS A 181 −20.255 −45.415 −6.564 1.00 119.69 A C ATOM 1376 C HIS A 181 −19.056 −48.314 −3.695 1.00 117.64 A C ATOM 1377 O HIS A 181 −17.902 −48.738 −3.552 1.00 117.82 A O ATOM 1378 N HIS A 182 −20.110 −49.103 −3.892 1.00 116.90 A N ATOM 1379 CA HIS A 182 −19.946 −50.516 −4.197 1.00 116.61 A C ATOM 1380 CB HIS A 182 −20.924 −51.381 −3.407 1.00 116.68 A C ATOM 1381 CG HIS A 182 −20.996 −51.045 −1.951 1.00 116.92 A C ATOM 1382 ND1 HIS A 182 −22.141 −51.222 −1.205 1.00 116.98 A N ATOM 1383 CE1 HIS A 182 −21.915 −50.843 0.039 1.00 117.13 A C ATOM 1384 NE2 HIS A 182 −20.668 −50.417 0.124 1.00 117.31 A N ATOM 1385 CD2 HIS A 182 −20.068 −50.542 −1.104 1.00 116.96 A C ATOM 1386 C HIS A 182 −20.172 −50.711 −5.683 1.00 116.30 A C ATOM 1387 O HIS A 182 −21.162 −50.229 −6.221 1.00 116.37 A O ATOM 1388 N TYR A 183 −19.257 −51.410 −6.345 1.00 115.91 A N ATOM 1389 CA TYR A 183 −19.351 −51.597 −7.783 1.00 115.59 A C ATOM 1390 CB TYR A 183 −18.004 −51.367 −8.452 1.00 115.48 A C ATOM 1391 CG TYR A 183 −17.325 −50.061 −8.116 1.00 115.78 A C ATOM 1392 CD1 TYR A 183 −15.975 −50.038 −7.766 1.00 116.65 A C ATOM 1393 CE1 TYR A 183 −15.326 −48.844 −7.469 1.00 116.84 A C ATOM 1394 CZ TYR A 183 −16.034 −47.653 −7.517 1.00 116.46 A C ATOM 1395 OH TYR A 183 −15.375 −46.484 −7.215 1.00 116.73 A O ATOM 1396 CE2 TYR A 183 −17.380 −47.645 −7.870 1.00 115.67 A C ATOM 1397 CD2 TYR A 183 −18.015 −48.848 −8.166 1.00 115.39 A C ATOM 1398 C TYR A 183 −19.846 −52.973 −8.171 1.00 115.62 A C ATOM 1399 O TYR A 183 −19.611 −53.950 −7.457 1.00 115.63 A O ATOM 1400 N GLY A 184 −20.542 −53.031 −9.304 1.00 115.57 A N ATOM 1401 CA GLY A 184 −20.787 −54.281 −10.026 1.00 115.67 A C ATOM 1402 C GLY A 184 −20.034 −54.184 −11.341 1.00 115.85 A C ATOM 1403 O GLY A 184 −19.654 −53.083 −11.748 1.00 116.15 A O ATOM 1404 N VAL A 185 −19.804 −55.313 −12.010 1.00 115.80 A N ATOM 1405 CA VAL A 185 −19.044 −55.317 −13.272 1.00 115.81 A C ATOM 1406 CB VAL A 185 −17.518 −55.359 −13.011 1.00 115.80 A C ATOM 1407 CG1 VAL A 185 −17.076 −56.700 −12.417 1.00 116.35 A C ATOM 1408 CG2 VAL A 185 −16.768 −55.075 −14.271 1.00 116.42 A C ATOM 1409 C VAL A 185 −19.466 −56.386 −14.297 1.00 115.87 A C ATOM 1410 O VAL A 185 −19.285 −57.598 −14.085 1.00 115.67 A O ATOM 1411 N GLU A 186 −20.015 −55.920 −15.417 1.00 116.18 A N ATOM 1412 CA GLU A 186 −20.541 −56.808 −16.466 1.00 116.46 A C ATOM 1413 CB GLU A 186 −22.044 −56.572 −16.635 1.00 116.05 A C ATOM 1414 CG GLU A 186 −22.712 −57.512 −17.616 1.00 115.22 A C ATOM 1415 CD GLU A 186 −22.916 −58.897 −17.045 1.00 114.43 A C ATOM 1416 OE1 GLU A 186 −23.105 −59.863 −17.821 1.00 114.59 A O ATOM 1417 OE2 GLU A 186 −22.880 −59.025 −15.809 1.00 113.03 A O ATOM 1418 C GLU A 186 −19.841 −56.633 −17.825 1.00 116.82 A C ATOM 1419 O GLU A 186 −19.753 −55.510 −18.335 1.00 117.07 A O ATOM 1420 N LYS A 187 −19.358 −57.734 −18.407 1.00 116.78 A N ATOM 1421 CA LYS A 187 −18.791 −57.708 −19.759 1.00 116.96 A C ATOM 1422 CB LYS A 187 −17.916 −58.943 −20.026 1.00 116.49 A C ATOM 1423 CG LYS A 187 −18.690 −60.273 −20.173 1.00 115.13 A C ATOM 1424 CD LYS A 187 −17.835 −61.509 −19.961 1.00 111.66 A C ATOM 1425 CE LYS A 187 −16.452 −61.341 −20.558 1.00 110.54 A C ATOM 1426 NZ LYS A 187 −15.650 −62.590 −20.439 1.00 110.61 A N ATOM 1427 C LYS A 187 −19.890 −57.570 −20.829 1.00 117.82 A C ATOM 1428 O LYS A 187 −19.894 −56.609 −21.604 1.00 118.10 A O ATOM 1429 N ALA A 188 −20.835 −58.512 −20.835 1.00 118.56 A N ATOM 1430 CA ALA A 188 −21.835 −58.645 −21.900 1.00 119.22 A C ATOM 1431 CB ALA A 188 −22.487 −60.029 −21.831 1.00 119.05 A C ATOM 1432 C ALA A 188 −22.911 −57.560 −21.888 1.00 119.73 A C ATOM 1433 O ALA A 188 −23.427 −57.211 −20.830 1.00 120.05 A O ATOM 1434 N ASP A 189 −23.248 −57.037 −23.070 1.00 120.41 A N ATOM 1435 CA ASP A 189 −24.433 −56.182 −23.245 1.00 120.80 A C ATOM 1436 CB ASP A 189 −24.507 −55.635 −24.674 1.00 120.73 A C ATOM 1437 CG ASP A 189 −23.508 −54.521 −24.931 0.50 121.31 A C ATOM 1438 OD1 ASP A 189 −23.930 −53.471 −25.465 0.50 121.74 A O ATOM 1439 OD2 ASP A 189 −22.308 −54.686 −24.608 0.50 121.55 A O ATOM 1440 C ASP A 189 −25.704 −56.973 −22.934 1.00 121.02 A C ATOM 1441 O ASP A 189 −25.752 −58.198 −23.123 1.00 121.02 A O ATOM 1442 N ILE A 190 −26.725 −56.269 −22.457 1.00 121.16 A N ATOM 1443 CA ILE A 190 −28.016 −56.879 −22.104 1.00 121.57 A C ATOM 1444 CB ILE A 190 −28.417 −58.094 −23.040 1.00 121.61 A C ATOM 1445 CG1 ILE A 190 −28.973 −57.569 −24.370 1.00 122.31 A C ATOM 1446 CD1 ILE A 190 −30.163 −56.566 −24.238 1.00 122.33 A C ATOM 1447 CG2 ILE A 190 −29.430 −59.044 −22.383 1.00 121.88 A C ATOM 1448 C ILE A 190 −28.165 −57.117 −20.586 1.00 121.52 A C ATOM 1449 O ILE A 190 −28.927 −56.379 −19.947 1.00 121.71 A O ATOM 1450 N PRO A 191 −27.433 −58.100 −19.992 1.00 121.32 A N ATOM 1451 CA PRO A 191 −27.423 −58.050 −18.536 1.00 121.10 A C ATOM 1452 CB PRO A 191 −26.406 −59.125 −18.165 1.00 120.97 A C ATOM 1453 CG PRO A 191 −26.504 −60.095 −19.260 1.00 121.02 A C ATOM 1454 CD PRO A 191 −26.649 −59.249 −20.483 1.00 121.26 A C ATOM 1455 C PRO A 191 −26.933 −56.669 −18.116 1.00 121.02 A C ATOM 1456 O PRO A 191 −27.480 −56.060 −17.187 1.00 120.91 A O ATOM 1457 N ALA A 192 −25.937 −56.178 −18.849 1.00 120.88 A N ATOM 1458 CA ALA A 192 −25.456 −54.816 −18.717 1.00 120.90 A C ATOM 1459 CB ALA A 192 −24.295 −54.581 −19.653 1.00 120.94 A C ATOM 1460 C ALA A 192 −26.542 −53.781 −18.973 1.00 120.92 A C ATOM 1461 O ALA A 192 −26.573 −52.750 −18.296 1.00 120.99 A O ATOM 1462 N LYS A 193 −27.416 −54.037 −19.949 1.00 120.89 A N ATOM 1463 CA LYS A 193 −28.392 −53.020 −20.337 1.00 120.94 A C ATOM 1464 CB LYS A 193 −28.899 −53.189 −21.769 1.00 121.13 A C ATOM 1465 CG LYS A 193 −29.418 −51.862 −22.363 1.00 121.57 A C ATOM 1466 CD LYS A 193 −30.216 −52.038 −23.665 1.00 122.00 A C ATOM 1467 CE LYS A 193 −31.673 −52.438 −23.423 1.00 121.21 A C ATOM 1468 NZ LYS A 193 −31.810 −53.872 −23.054 1.00 120.87 A N ATOM 1469 C LYS A 193 −29.544 −52.964 −19.365 1.00 120.80 A C ATOM 1470 O LYS A 193 −29.986 −51.876 −18.988 1.00 120.78 A O ATOM 1471 N TYR A 194 −30.020 −54.137 −18.954 1.00 120.62 A N ATOM 1472 CA TYR A 194 −31.013 −54.215 −17.890 1.00 120.56 A C ATOM 1473 CB TYR A 194 −31.475 −55.655 −17.655 1.00 120.57 A C ATOM 1474 CG TYR A 194 −32.246 −56.279 −18.810 1.00 121.31 A C ATOM 1475 CD1 TYR A 194 −33.095 −55.511 −19.623 1.00 122.05 A C ATOM 1476 CE1 TYR A 194 −33.809 −56.089 −20.676 1.00 122.46 A C ATOM 1477 CZ TYR A 194 −33.682 −57.451 −20.916 1.00 123.31 A C ATOM 1478 OH TYR A 194 −34.377 −58.046 −21.950 1.00 124.42 A O ATOM 1479 CE2 TYR A 194 −32.856 −58.232 −20.117 1.00 122.66 A C ATOM 1480 CD2 TYR A 194 −32.149 −57.645 −19.072 1.00 121.80 A C ATOM 1481 C TYR A 194 −30.457 −53.590 −16.611 1.00 120.30 A C ATOM 1482 O TYR A 194 −31.135 −52.796 −15.958 1.00 120.27 A O ATOM 1483 N ALA A 195 −29.207 −53.910 −16.287 1.00 119.98 A N ATOM 1484 CA ALA A 195 −28.512 −53.254 −15.183 1.00 119.75 A C ATOM 1485 CB ALA A 195 −27.052 −53.581 −15.221 1.00 119.76 A C ATOM 1486 C ALA A 195 −28.702 −51.739 −15.168 1.00 119.74 A C ATOM 1487 O ALA A 195 −28.616 −51.118 −14.110 1.00 119.86 A O ATOM 1488 N GLU A 196 −28.961 −51.145 −16.333 1.00 119.62 A N ATOM 1489 CA GLU A 196 −29.099 −49.689 −16.430 1.00 119.52 A C ATOM 1490 CB GLU A 196 −28.820 −49.204 −17.850 1.00 119.63 A C ATOM 1491 CG GLU A 196 −27.351 −49.006 −18.150 1.00 121.03 A C ATOM 1492 CD GLU A 196 −27.057 −48.974 −19.639 1.00 122.77 A C ATOM 1493 OE1 GLU A 196 −27.477 −49.926 −20.346 1.00 123.35 A O ATOM 1494 OE2 GLU A 196 −26.400 −48.002 −20.094 1.00 122.42 A O ATOM 1495 C GLU A 196 −30.462 −49.206 −15.967 1.00 119.08 A C ATOM 1496 O GLU A 196 −30.581 −48.136 −15.357 1.00 118.95 A O ATOM 1497 N THR A 197 −31.491 −49.990 −16.277 1.00 118.57 A N ATOM 1498 CA THR A 197 −32.840 −49.682 −15.821 1.00 118.04 A C ATOM 1499 CB THR A 197 −33.911 −50.366 −16.673 1.00 117.83 A C ATOM 1500 OG1 THR A 197 −33.365 −51.545 −17.267 1.00 117.85 A O ATOM 1501 CG2 THR A 197 −34.338 −49.449 −17.776 1.00 118.30 A C ATOM 1502 C THR A 197 −32.997 −50.061 −14.354 1.00 117.68 A C ATOM 1503 O THR A 197 −33.696 −49.363 −13.603 1.00 117.87 A O ATOM 1504 N MET A 198 −32.326 −51.150 −13.954 1.00 116.83 A N ATOM 1505 CA MET A 198 −32.321 −51.617 −12.565 1.00 115.79 A C ATOM 1506 CB MET A 198 −31.492 −52.891 −12.417 1.00 115.62 A C ATOM 1507 CG MET A 198 −32.140 −54.125 −12.999 1.00 115.16 A C ATOM 1508 SD MET A 198 −33.212 −54.988 −11.832 1.00 115.70 A S ATOM 1509 CE MET A 198 −32.296 −56.491 −11.518 1.00 114.02 A C ATOM 1510 C MET A 198 −31.787 −50.513 −11.662 1.00 115.30 A C ATOM 1511 O MET A 198 −32.407 −50.164 −10.663 1.00 115.13 A O ATOM 1512 N ASP A 199 −30.649 −49.945 −12.042 1.00 114.78 A N ATOM 1513 CA ASP A 199 −30.106 −48.795 −11.352 1.00 114.49 A C ATOM 1514 CB ASP A 199 −28.990 −48.168 −12.199 1.00 114.49 A C ATOM 1515 CG ASP A 199 −28.398 −46.899 −11.580 1.00 114.62 A C ATOM 1516 OD1 ASP A 199 −29.155 −46.019 −11.106 1.00 114.42 A O ATOM 1517 OD2 ASP A 199 −27.154 −46.769 −11.600 1.00 115.05 A O ATOM 1518 C ASP A 199 −31.240 −47.804 −11.092 1.00 114.33 A C ATOM 1519 O ASP A 199 −31.494 −47.428 −9.947 1.00 114.33 A O ATOM 1520 N ARG A 200 −31.940 −47.414 −12.153 1.00 114.07 A N ATOM 1521 CA ARG A 200 −32.932 −46.355 −12.057 1.00 113.96 A C ATOM 1522 CB ARG A 200 −33.461 −45.973 −13.440 1.00 114.31 A C ATOM 1523 CG ARG A 200 −32.411 −45.390 −14.368 1.00 116.73 A C ATOM 1524 CD ARG A 200 −33.044 −44.603 −15.534 1.00 120.46 A C ATOM 1525 NE ARG A 200 −32.155 −44.582 −16.701 1.00 122.27 A N ATOM 1526 CZ ARG A 200 −32.205 −45.459 −17.706 1.00 123.10 A C ATOM 1527 NH1 ARG A 200 −33.113 −46.430 −17.720 1.00 123.10 A N ATOM 1528 NH2 ARG A 200 −31.345 −45.360 −18.711 1.00 123.39 A N ATOM 1529 C ARG A 200 −34.083 −46.728 −11.130 1.00 113.15 A C ATOM 1530 O ARG A 200 −34.381 −46.005 −10.172 1.00 113.00 A O ATOM 1531 N GLU A 201 −34.714 −47.864 −11.412 1.00 112.21 A N ATOM 1532 CA GLU A 201 −35.940 −48.246 −10.720 1.00 111.28 A C ATOM 1533 CB GLU A 201 −36.543 −49.505 −11.338 1.00 111.13 A C ATOM 1534 CG GLU A 201 −37.504 −49.196 −12.471 1.00 111.12 A C ATOM 1535 CD GLU A 201 −38.923 −48.924 −11.990 1.00 111.43 A C ATOM 1536 OE1 GLU A 201 −39.552 −49.865 −11.455 1.00 111.69 A O ATOM 1537 OE2 GLU A 201 −39.418 −47.781 −12.159 1.00 111.10 A O ATOM 1538 C GLU A 201 −35.726 −48.396 −9.222 1.00 110.69 A C ATOM 1539 O GLU A 201 −36.505 −47.869 −8.425 1.00 110.74 A O ATOM 1540 N PHE A 202 −34.654 −49.091 −8.854 1.00 109.73 A N ATOM 1541 CA PHE A 202 −34.216 −49.188 −7.470 1.00 108.66 A C ATOM 1542 CB PHE A 202 −32.872 −49.901 −7.412 1.00 108.66 A C ATOM 1543 CG PHE A 202 −32.245 −49.910 −6.058 1.00 108.42 A C ATOM 1544 CD1 PHE A 202 −32.506 −50.943 −5.170 1.00 108.11 A C ATOM 1545 CE1 PHE A 202 −31.924 −50.964 −3.916 1.00 108.00 A C ATOM 1546 CZ PHE A 202 −31.063 −49.945 −3.542 1.00 108.70 A C ATOM 1547 CE2 PHE A 202 −30.783 −48.903 −4.430 1.00 108.52 A C ATOM 1548 CD2 PHE A 202 −31.371 −48.895 −5.678 1.00 108.42 A C ATOM 1549 C PHE A 202 −34.118 −47.810 −6.826 1.00 107.99 A C ATOM 1550 O PHE A 202 −34.761 −47.546 −5.813 1.00 107.92 A O ATOM 1551 N ARG A 203 −33.329 −46.927 −7.424 1.00 107.24 A N ATOM 1552 CA ARG A 203 −33.203 −45.569 −6.897 1.00 106.81 A C ATOM 1553 CB ARG A 203 −32.216 −44.736 −7.730 1.00 107.08 A C ATOM 1554 CG ARG A 203 −30.871 −44.517 −7.054 1.00 107.58 A C ATOM 1555 CD ARG A 203 −29.999 −43.561 −7.842 1.00 109.67 A C ATOM 1556 NE ARG A 203 −29.332 −42.582 −6.974 1.00 111.39 A N ATOM 1557 CZ ARG A 203 −29.803 −41.364 −6.681 1.00 112.22 A C ATOM 1558 NH1 ARG A 203 −30.964 −40.932 −7.178 1.00 112.19 A N ATOM 1559 NH2 ARG A 203 −29.106 −40.564 −5.881 1.00 112.60 A N ATOM 1560 C ARG A 203 −34.562 −44.866 −6.753 1.00 106.05 A C ATOM 1561 O ARG A 203 −34.808 −44.201 −5.744 1.00 106.01 A O ATOM 1562 N LYS A 204 −35.429 −45.038 −7.755 1.00 105.03 A N ATOM 1563 CA LYS A 204 −36.780 −44.481 −7.755 1.00 103.96 A C ATOM 1564 CB LYS A 204 −37.513 −44.881 −9.043 1.00 103.96 A C ATOM 1565 CG LYS A 204 −38.958 −44.366 −9.161 1.00 103.08 A C ATOM 1566 CD LYS A 204 −39.861 −45.332 −9.934 1.00 101.05 A C ATOM 1567 CE LYS A 204 −41.336 −45.048 −9.634 1.00 100.77 A C ATOM 1568 NZ LYS A 204 −42.221 −46.250 −9.779 1.00 99.07 A N ATOM 1569 C LYS A 204 −37.566 −44.978 −6.550 1.00 103.53 A C ATOM 1570 O LYS A 204 −38.099 −44.183 −5.772 1.00 103.25 A O ATOM 1571 N TRP A 205 −37.624 −46.302 −6.410 1.00 103.06 A N ATOM 1572 CA TRP A 205 −38.439 −46.960 −5.387 1.00 102.47 A C ATOM 1573 CB TRP A 205 −38.578 −48.448 −5.675 1.00 102.29 A C ATOM 1574 CG TRP A 205 −39.519 −48.757 −6.797 1.00 102.22 A C ATOM 1575 CD1 TRP A 205 −39.190 −49.037 −8.089 1.00 102.24 A C ATOM 1576 NE1 TRP A 205 −40.322 −49.286 −8.829 1.00 101.90 A N ATOM 1577 CE2 TRP A 205 −41.412 −49.165 −8.014 1.00 102.02 A C ATOM 1578 CD2 TRP A 205 −40.944 −48.834 −6.723 1.00 101.92 A C ATOM 1579 CE3 TRP A 205 −41.872 −48.651 −5.694 1.00 101.93 A C ATOM 1580 CZ3 TRP A 205 −43.219 −48.805 −5.978 1.00 102.20 A C ATOM 1581 CH2 TRP A 205 −43.653 −49.133 −7.268 1.00 103.28 A C ATOM 1582 CZ2 TRP A 205 −42.764 −49.316 −8.302 1.00 102.98 A C ATOM 1583 C TRP A 205 −37.923 −46.761 −3.972 1.00 102.18 A C ATOM 1584 O TRP A 205 −38.716 −46.686 −3.034 1.00 102.48 A O ATOM 1585 N MET A 206 −36.608 −46.669 −3.804 1.00 101.40 A N ATOM 1586 CA MET A 206 −36.079 −46.321 −2.497 1.00 100.76 A C ATOM 1587 CB MET A 206 −34.560 −46.268 −2.518 1.00 100.73 A C ATOM 1588 CG MET A 206 −33.930 −47.630 −2.740 1.00 101.36 A C ATOM 1589 SD MET A 206 −34.050 −48.770 −1.347 1.00 101.98 A S ATOM 1590 CE MET A 206 −32.528 −48.338 −0.501 1.00 101.91 A C ATOM 1591 C MET A 206 −36.688 −44.991 −2.084 1.00 100.35 A C ATOM 1592 O MET A 206 −37.366 −44.906 −1.064 1.00 100.12 A O ATOM 1593 N LYS A 207 −36.474 −43.975 −2.916 1.00 100.08 A N ATOM 1594 CA LYS A 207 −37.096 −42.667 −2.761 1.00 99.70 A C ATOM 1595 CB LYS A 207 −36.873 −41.821 −4.019 1.00 99.90 A C ATOM 1596 CG LYS A 207 −35.529 −41.111 −4.139 1.00 100.14 A C ATOM 1597 CD LYS A 207 −35.576 −40.137 −5.317 1.00 101.25 A C ATOM 1598 CE LYS A 207 −34.824 −38.834 −5.043 1.00 102.53 A C ATOM 1599 NZ LYS A 207 −35.447 −37.652 −5.745 1.00 101.98 A N ATOM 1600 C LYS A 207 −38.595 −42.804 −2.512 1.00 99.28 A C ATOM 1601 O LYS A 207 −39.138 −42.173 −1.603 1.00 99.44 A O ATOM 1602 N TRP A 208 −39.257 −43.634 −3.315 1.00 98.59 A N ATOM 1603 CA TRP A 208 −40.698 −43.836 −3.185 1.00 98.15 A C ATOM 1604 CB TRP A 208 −41.233 −44.757 −4.295 1.00 98.20 A C ATOM 1605 CG TRP A 208 −42.732 −44.649 −4.492 1.00 97.16 A C ATOM 1606 CD1 TRP A 208 −43.397 −43.751 −5.292 1.00 97.28 A C ATOM 1607 NE1 TRP A 208 −44.756 −43.944 −5.197 1.00 96.30 A N ATOM 1608 CE2 TRP A 208 −44.992 −44.981 −4.333 1.00 95.28 A C ATOM 1609 CD2 TRP A 208 −43.739 −45.449 −3.871 1.00 94.80 A C ATOM 1610 CE3 TRP A 208 −43.708 −46.511 −2.971 1.00 93.47 A C ATOM 1611 CZ3 TRP A 208 −44.906 −47.071 −2.563 1.00 93.20 A C ATOM 1612 CH2 TRP A 208 −46.132 −46.592 −3.041 1.00 93.91 A C ATOM 1613 CZ2 TRP A 208 −46.196 −45.549 −3.927 1.00 94.41 A C ATOM 1614 C TRP A 208 −41.086 −44.384 −1.813 1.00 97.98 A C ATOM 1615 O TRP A 208 −42.187 −44.127 −1.334 1.00 97.67 A O ATOM 1616 N TYR A 209 −40.167 −45.127 −1.191 1.00 97.95 A N ATOM 1617 CA TYR A 209 −40.391 −45.745 0.124 1.00 97.63 A C ATOM 1618 CB TYR A 209 −39.798 −47.139 0.146 1.00 96.50 A C ATOM 1619 CG TYR A 209 −40.619 −48.193 −0.539 1.00 93.33 A C ATOM 1620 CD1 TYR A 209 −41.826 −48.637 0.000 1.00 89.99 A C ATOM 1621 CE1 TYR A 209 −42.564 −49.631 −0.622 1.00 86.87 A C ATOM 1622 CZ TYR A 209 −42.087 −50.196 −1.790 1.00 85.75 A C ATOM 1623 OH TYR A 209 −42.774 −51.190 −2.427 1.00 83.47 A O ATOM 1624 CE2 TYR A 209 −40.898 −49.783 −2.331 1.00 87.79 A C ATOM 1625 CD2 TYR A 209 −40.166 −48.791 −1.703 1.00 90.72 A C ATOM 1626 C TYR A 209 −39.815 −44.968 1.311 1.00 98.60 A C ATOM 1627 O TYR A 209 −40.065 −45.322 2.460 1.00 98.54 A O ATOM 1628 N GLY A 210 −39.044 −43.923 1.027 1.00 99.66 A N ATOM 1629 CA GLY A 210 −38.359 −43.150 2.059 1.00 101.20 A C ATOM 1630 C GLY A 210 −37.095 −43.807 2.598 1.00 102.39 A C ATOM 1631 O GLY A 210 −36.742 −43.616 3.763 1.00 102.56 A O ATOM 1632 N LYS A 211 −36.404 −44.580 1.763 1.00 103.35 A N ATOM 1633 CA LYS A 211 −35.270 −45.363 2.247 1.00 104.29 A C ATOM 1634 CB LYS A 211 −35.512 −46.863 2.094 1.00 104.23 A C ATOM 1635 CG LYS A 211 −36.657 −47.423 2.940 1.00 104.42 A C ATOM 1636 CD LYS A 211 −36.666 −46.934 4.389 1.00 104.29 A C ATOM 1637 CE LYS A 211 −37.691 −47.730 5.190 1.00 105.06 A C ATOM 1638 NZ LYS A 211 −38.350 −46.951 6.276 1.00 105.66 A N ATOM 1639 C LYS A 211 −33.961 −44.985 1.604 1.00 105.08 A C ATOM 1640 O LYS A 211 −33.927 −44.478 0.481 1.00 105.23 A O ATOM 1641 N LYS A 212 −32.883 −45.246 2.338 1.00 106.18 A N ATOM 1642 CA LYS A 212 −31.553 −44.795 1.953 1.00 107.24 A C ATOM 1643 CB LYS A 212 −30.941 −43.922 3.055 1.00 107.38 A C ATOM 1644 CG LYS A 212 −30.584 −44.656 4.344 1.00 108.37 A C ATOM 1645 CD LYS A 212 −29.317 −44.061 4.932 1.00 110.33 A C ATOM 1646 CE LYS A 212 −29.045 −44.555 6.335 1.00 111.08 A C ATOM 1647 NZ LYS A 212 −28.434 −43.443 7.125 1.00 111.60 A N ATOM 1648 C LYS A 212 −30.623 −45.952 1.588 1.00 107.59 A C ATOM 1649 O LYS A 212 −30.681 −47.029 2.184 1.00 107.48 A O ATOM 1650 N HIS A 213 −29.773 −45.710 0.598 1.00 108.09 A N ATOM 1651 CA HIS A 213 −28.835 −46.715 0.132 1.00 108.71 A C ATOM 1652 CB HIS A 213 −29.208 −47.213 −1.272 1.00 108.63 A C ATOM 1653 CG HIS A 213 −29.145 −46.154 −2.331 1.00 108.64 A C ATOM 1654 ND1 HIS A 213 −27.984 −45.841 −3.004 1.00 108.18 A N ATOM 1655 CE1 HIS A 213 −28.225 −44.870 −3.866 1.00 108.50 A C ATOM 1656 NE2 HIS A 213 −29.503 −44.547 −3.784 1.00 108.75 A N ATOM 1657 CD2 HIS A 213 −30.102 −45.337 −2.833 1.00 108.68 A C ATOM 1658 C HIS A 213 −27.450 −46.116 0.113 1.00 109.12 A C ATOM 1659 O HIS A 213 −27.301 −44.902 −0.002 1.00 109.32 A O ATOM 1660 N ALA A 214 −26.443 −46.977 0.226 1.00 109.69 A N ATOM 1661 CA ALA A 214 −25.053 −46.583 0.053 1.00 110.09 A C ATOM 1662 CB ALA A 214 −24.131 −47.744 0.387 1.00 110.06 A C ATOM 1663 C ALA A 214 −24.865 −46.146 −1.387 1.00 110.39 A C ATOM 1664 O ALA A 214 −25.802 −46.185 −2.175 1.00 110.67 A O ATOM 1665 N GLU A 215 −23.664 −45.713 −1.732 1.00 110.82 A N ATOM 1666 CA GLU A 215 −23.376 −45.333 −3.098 1.00 111.51 A C ATOM 1667 CB GLU A 215 −22.167 −44.401 −3.148 1.00 111.88 A C ATOM 1668 CG GLU A 215 −22.260 −43.176 −2.216 1.00 114.33 A C ATOM 1669 CD GLU A 215 −21.817 −43.472 −0.777 1.00 117.27 A C ATOM 1670 OE1 GLU A 215 −20.764 −42.939 −0.362 1.00 119.27 A O ATOM 1671 OE2 GLU A 215 −22.507 −44.238 −0.063 1.00 117.73 A O ATOM 1672 C GLU A 215 −23.102 −46.620 −3.846 1.00 111.39 A C ATOM 1673 O GLU A 215 −22.531 −47.543 −3.276 1.00 111.69 A O ATOM 1674 N TYR A 216 −23.534 −46.709 −5.101 1.00 111.40 A N ATOM 1675 CA TYR A 216 −23.268 −47.907 −5.907 1.00 111.42 A C ATOM 1676 CB TYR A 216 −24.370 −48.958 −5.723 1.00 111.26 A C ATOM 1677 CG TYR A 216 −25.654 −48.586 −6.399 1.00 111.37 A C ATOM 1678 CD1 TYR A 216 −25.891 −48.946 −7.725 1.00 111.76 A C ATOM 1679 CE1 TYR A 216 −27.073 −48.592 −8.366 1.00 112.01 A C ATOM 1680 CZ TYR A 216 −28.033 −47.873 −7.675 1.00 111.92 A C ATOM 1681 OH TYR A 216 −29.200 −47.525 −8.307 1.00 112.07 A O ATOM 1682 CE2 TYR A 216 −27.822 −47.504 −6.354 1.00 112.17 A C ATOM 1683 CD2 TYR A 216 −26.631 −47.858 −5.725 1.00 111.63 A C ATOM 1684 C TYR A 216 −23.088 −47.598 −7.387 1.00 111.36 A C ATOM 1685 O TYR A 216 −23.651 −46.635 −7.902 1.00 111.49 A O ATOM 1686 N THR A 217 −22.324 −48.443 −8.068 1.00 111.37 A N ATOM 1687 CA THR A 217 −22.047 −48.265 −9.486 1.00 111.41 A C ATOM 1688 CB THR A 217 −20.726 −47.523 −9.694 1.00 111.32 A C ATOM 1689 OG1 THR A 217 −20.949 −46.118 −9.536 1.00 111.25 A O ATOM 1690 CG2 THR A 217 −20.171 −47.780 −11.077 1.00 111.13 A C ATOM 1691 C THR A 217 −22.036 −49.581 −10.251 1.00 111.65 A C ATOM 1692 O THR A 217 −21.378 −50.545 −9.858 1.00 111.68 A O ATOM 1693 N LEU A 218 −22.775 −49.607 −11.353 1.00 112.05 A N ATOM 1694 CA LEU A 218 −22.855 −50.790 −12.200 1.00 112.30 A C ATOM 1695 CB LEU A 218 −24.314 −51.237 −12.335 1.00 112.21 A C ATOM 1696 CG LEU A 218 −25.184 −51.254 −11.067 1.00 112.03 A C ATOM 1697 CD1 LEU A 218 −26.585 −51.709 −11.388 1.00 112.90 A C ATOM 1698 CD2 LEU A 218 −24.615 −52.153 −10.009 1.00 112.35 A C ATOM 1699 C LEU A 218 −22.236 −50.472 −13.558 1.00 112.47 A C ATOM 1700 O LEU A 218 −22.729 −49.597 −14.267 1.00 112.55 A O ATOM 1701 N GLU A 219 −21.153 −51.168 −13.903 1.00 112.67 A N ATOM 1702 CA GLU A 219 −20.351 −50.824 −15.081 1.00 113.16 A C ATOM 1703 CB GLU A 219 −18.926 −50.461 −14.672 1.00 113.15 A C ATOM 1704 CG GLU A 219 −18.785 −49.542 −13.481 1.00 113.45 A C ATOM 1705 CD GLU A 219 −17.333 −49.355 −13.067 1.00 113.68 A C ATOM 1706 OE1 GLU A 219 −16.461 −50.073 −13.610 1.00 114.20 A O ATOM 1707 OE2 GLU A 219 −17.062 −48.494 −12.200 1.00 113.06 A O ATOM 1708 C GLU A 219 −20.240 −51.934 −16.116 1.00 113.60 A C ATOM 1709 O GLU A 219 −20.418 −53.116 −15.804 1.00 113.73 A O ATOM 1710 N ARG A 220 −19.926 −51.543 −17.351 1.00 114.14 A N ATOM 1711 CA ARG A 220 −19.395 −52.486 −18.334 1.00 114.73 A C ATOM 1712 CB ARG A 220 −19.331 −51.879 −19.745 1.00 114.91 A C ATOM 1713 CG ARG A 220 −20.512 −52.208 −20.662 1.00 115.91 A C ATOM 1714 CD ARG A 220 −21.272 −50.947 −21.115 1.00 117.92 A C ATOM 1715 NE ARG A 220 −20.449 −50.069 −21.966 1.00 119.22 A N ATOM 1716 CZ ARG A 220 −20.883 −48.972 −22.595 1.00 119.15 A C ATOM 1717 NH1 ARG A 220 −20.040 −48.260 −23.328 1.00 118.56 A N ATOM 1718 NH2 ARG A 220 −22.150 −48.580 −22.499 1.00 119.31 A N ATOM 1719 C ARG A 220 −17.991 −52.875 −17.883 1.00 114.69 A C ATOM 1720 O ARG A 220 −17.226 −52.033 −17.408 1.00 114.74 A O ATOM 1721 N GLY A 221 −17.649 −54.149 −18.015 1.00 114.72 A N ATOM 1722 CA GLY A 221 −16.304 −54.576 −17.677 1.00 114.94 A C ATOM 1723 C GLY A 221 −16.045 −56.067 −17.632 1.00 115.22 A C ATOM 1724 O GLY A 221 −16.862 −56.859 −17.143 1.00 114.82 A O ATOM 1725 N ASP A 222 −14.891 −56.436 −18.181 1.00 115.53 A N ATOM 1726 CA ASP A 222 −14.304 −57.732 −17.940 1.00 115.67 A C ATOM 1727 CB ASP A 222 −13.484 −58.192 −19.137 1.00 115.52 A C ATOM 1728 CG ASP A 222 −13.171 −59.668 −19.083 1.00 116.10 A C ATOM 1729 OD1 ASP A 222 −12.594 −60.118 −18.067 1.00 116.19 A O ATOM 1730 OD2 ASP A 222 −13.503 −60.383 −20.057 1.00 116.68 A O ATOM 1731 C ASP A 222 −13.415 −57.489 −16.739 1.00 115.89 A C ATOM 1732 O ASP A 222 −12.617 −56.530 −16.726 1.00 116.09 A O ATOM 1733 N PHE A 223 −13.566 −58.315 −15.706 1.00 115.66 A N ATOM 1734 CA PHE A 223 −12.842 −58.023 −14.473 1.00 115.12 A C ATOM 1735 CB PHE A 223 −13.537 −58.563 −13.213 1.00 114.39 A C ATOM 1736 CG PHE A 223 −14.170 −59.914 −13.364 1.00 111.02 A C ATOM 1737 CD1 PHE A 223 −13.397 −61.053 −13.480 1.00 108.84 A C ATOM 1738 CE1 PHE A 223 −13.996 −62.300 −13.580 1.00 107.20 A C ATOM 1739 CZ PHE A 223 −15.376 −62.412 −13.540 1.00 105.58 A C ATOM 1740 CE2 PHE A 223 −16.149 −61.295 −13.403 1.00 105.06 A C ATOM 1741 CD2 PHE A 223 −15.549 −60.052 −13.307 1.00 108.11 A C ATOM 1742 C PHE A 223 −11.357 −58.366 −14.523 1.00 115.72 A C ATOM 1743 O PHE A 223 −10.563 −57.768 −13.798 1.00 115.89 A O ATOM 1744 N LEU A 224 −10.989 −59.297 −15.404 1.00 116.28 A N ATOM 1745 CA LEU A 224 −9.591 −59.678 −15.602 1.00 116.70 A C ATOM 1746 CB LEU A 224 −9.474 −60.876 −16.543 1.00 116.61 A C ATOM 1747 CG LEU A 224 −10.369 −62.108 −16.377 1.00 116.89 A C ATOM 1748 CD1 LEU A 224 −10.136 −63.070 −17.529 1.00 117.22 A C ATOM 1749 CD2 LEU A 224 −10.150 −62.818 −15.054 1.00 117.01 A C ATOM 1750 C LEU A 224 −8.764 −58.521 −16.153 1.00 117.22 A C ATOM 1751 O LEU A 224 −7.544 −58.505 −15.996 1.00 117.32 A O ATOM 1752 N SER A 225 −9.426 −57.550 −16.783 1.00 117.76 A N ATOM 1753 CA SER A 225 −8.736 −56.412 −17.395 1.00 118.40 A C ATOM 1754 CB SER A 225 −9.734 −55.385 −17.933 1.00 118.48 A C ATOM 1755 OG SER A 225 −10.294 −54.612 −16.884 1.00 118.97 A O ATOM 1756 C SER A 225 −7.716 −55.724 −16.484 1.00 118.70 A C ATOM 1757 O SER A 225 −7.829 −55.733 −15.256 1.00 118.76 A O ATOM 1758 N GLU A 226 −6.722 −55.128 −17.128 1.00 119.35 A N ATOM 1759 CA GLU A 226 −5.625 −54.399 −16.484 1.00 119.83 A C ATOM 1760 CB GLU A 226 −4.683 −53.794 −17.554 1.00 120.12 A C ATOM 1761 CG GLU A 226 −5.384 −53.174 −18.802 1.00 120.79 A C ATOM 1762 CD GLU A 226 −6.189 −54.195 −19.630 1.00 121.68 A C ATOM 1763 OE1 GLU A 226 −5.692 −55.326 −19.852 1.00 121.37 A O ATOM 1764 OE2 GLU A 226 −7.325 −53.864 −20.043 1.00 121.68 A O ATOM 1765 C GLU A 226 −6.080 −53.339 −15.471 1.00 119.63 A C ATOM 1766 O GLU A 226 −5.453 −53.170 −14.429 1.00 119.30 A O ATOM 1767 N GLU A 227 −7.170 −52.642 −15.778 1.00 119.81 A N ATOM 1768 CA GLU A 227 −7.722 −51.637 −14.865 1.00 120.24 A C ATOM 1769 CB GLU A 227 −8.847 −50.833 −15.539 1.00 120.25 A C ATOM 1770 CG GLU A 227 −9.402 −49.661 −14.711 1.00 120.07 A C ATOM 1771 CD GLU A 227 −10.862 −49.316 −15.050 1.00 120.33 A C ATOM 1772 OE1 GLU A 227 −11.372 −48.288 −14.540 1.00 119.81 A O ATOM 1773 OE2 GLU A 227 −11.504 −50.071 −15.821 1.00 119.75 A O ATOM 1774 C GLU A 227 −8.228 −52.288 −13.578 1.00 120.44 A C ATOM 1775 O GLU A 227 −7.964 −51.791 −12.480 1.00 120.51 A O ATOM 1776 N TRP A 228 −8.947 −53.401 −13.722 1.00 120.55 A N ATOM 1777 CA TRP A 228 −9.501 −54.107 −12.572 1.00 120.75 A C ATOM 1778 CB TRP A 228 −10.586 −55.114 −12.973 1.00 121.23 A C ATOM 1779 CG TRP A 228 −11.934 −54.460 −13.134 1.00 123.00 A C ATOM 1780 CD1 TRP A 228 −12.587 −54.191 −14.306 1.00 124.02 A C ATOM 1781 NE1 TRP A 228 −13.784 −53.560 −14.047 1.00 124.34 A N ATOM 1782 CE2 TRP A 228 −13.920 −53.403 −12.692 1.00 124.56 A C ATOM 1783 CD2 TRP A 228 −12.774 −53.956 −12.083 1.00 124.32 A C ATOM 1784 CE3 TRP A 228 −12.671 −53.928 −10.686 1.00 124.96 A C ATOM 1785 CZ3 TRP A 228 −13.704 −53.357 −9.949 1.00 125.13 A C ATOM 1786 CH2 TRP A 228 −14.831 −52.819 −10.583 1.00 125.12 A C ATOM 1787 CZ2 TRP A 228 −14.957 −52.829 −11.950 1.00 125.25 A C ATOM 1788 C TRP A 228 −8.433 −54.750 −11.717 1.00 120.30 A C ATOM 1789 O TRP A 228 −8.555 −54.738 −10.497 1.00 120.42 A O ATOM 1790 N ARG A 229 −7.384 −55.283 −12.344 1.00 119.89 A N ATOM 1791 CA ARG A 229 −6.187 −55.723 −11.608 1.00 119.57 A C ATOM 1792 CB ARG A 229 −4.927 −55.661 −12.487 1.00 119.57 A C ATOM 1793 CG ARG A 229 −4.898 −56.584 −13.684 1.00 119.56 A C ATOM 1794 CD ARG A 229 −3.468 −56.987 −14.029 1.00 119.51 A C ATOM 1795 NE ARG A 229 −3.128 −58.308 −13.499 1.00 120.11 A N ATOM 1796 CZ ARG A 229 −3.259 −59.449 −14.179 1.00 121.00 A C ATOM 1797 NH1 ARG A 229 −3.715 −59.435 −15.423 1.00 121.68 A N ATOM 1798 NH2 ARG A 229 −2.933 −60.615 −13.626 1.00 121.47 A N ATOM 1799 C ARG A 229 −5.945 −54.848 −10.371 1.00 119.20 A C ATOM 1800 O ARG A 229 −5.818 −55.357 −9.255 1.00 118.94 A O ATOM 1801 N GLU A 230 −5.902 −53.534 −10.602 1.00 118.85 A N ATOM 1802 CA GLU A 230 −5.614 −52.532 −9.574 1.00 118.67 A C ATOM 1803 CB GLU A 230 −5.223 −51.174 −10.199 1.00 118.91 A C ATOM 1804 CG GLU A 230 −4.362 −51.224 −11.465 1.00 120.28 A C ATOM 1805 CD GLU A 230 −2.876 −51.516 −11.207 1.00 122.49 A C ATOM 1806 OE1 GLU A 230 −2.164 −50.640 −10.653 1.00 122.69 A O ATOM 1807 OE2 GLU A 230 −2.414 −52.617 −11.596 1.00 122.89 A O ATOM 1808 C GLU A 230 −6.778 −52.313 −8.604 1.00 117.96 A C ATOM 1809 O GLU A 230 −6.552 −51.951 −7.448 1.00 118.21 A O ATOM 1810 N ARG A 231 −8.010 −52.508 −9.075 1.00 116.91 A N ATOM 1811 CA ARG A 231 −9.203 −52.244 −8.253 1.00 115.92 A C ATOM 1812 CB ARG A 231 −10.400 −51.884 −9.131 1.00 116.02 A C ATOM 1813 CG ARG A 231 −10.312 −50.492 −9.729 1.00 116.70 A C ATOM 1814 CD ARG A 231 −11.218 −50.343 −10.935 1.00 117.76 A C ATOM 1815 NE ARG A 231 −12.609 −50.092 −10.568 1.00 118.42 A N ATOM 1816 CZ ARG A 231 −13.560 −49.754 −11.434 1.00 118.53 A C ATOM 1817 NH1 ARG A 231 −13.274 −49.626 −12.722 1.00 119.04 A N ATOM 1818 NH2 ARG A 231 −14.799 −49.537 −11.016 1.00 118.29 A N ATOM 1819 C ARG A 231 −9.553 −53.389 −7.299 1.00 114.95 A C ATOM 1820 O ARG A 231 −9.796 −53.161 −6.111 1.00 114.70 A O ATOM 1821 N ILE A 232 −9.568 −54.610 −7.830 1.00 113.75 A N ATOM 1822 CA ILE A 232 −9.705 −55.831 −7.033 1.00 112.68 A C ATOM 1823 CB ILE A 232 −9.545 −57.086 −7.919 1.00 112.67 A C ATOM 1824 CG1 ILE A 232 −10.384 −56.954 −9.190 1.00 112.94 A C ATOM 1825 CD1 ILE A 232 −9.914 −57.833 −10.335 1.00 114.15 A C ATOM 1826 CG2 ILE A 232 −9.920 −58.351 −7.164 1.00 112.12 A C ATOM 1827 C ILE A 232 −8.657 −55.873 −5.922 1.00 112.13 A C ATOM 1828 O ILE A 232 −8.865 −56.497 −4.885 1.00 111.89 A O ATOM 1829 N ALA A 233 −7.528 −55.207 −6.159 1.00 111.51 A N ATOM 1830 CA ALA A 233 −6.454 −55.097 −5.182 1.00 110.75 A C ATOM 1831 CB ALA A 233 −5.220 −54.518 −5.836 1.00 110.61 A C ATOM 1832 C ALA A 233 −6.872 −54.250 −3.974 1.00 110.25 A C ATOM 1833 O ALA A 233 −6.483 −54.537 −2.847 1.00 110.40 A O ATOM 1834 N ASN A 234 −7.673 −53.220 −4.208 1.00 109.39 A N ATOM 1835 CA ASN A 234 −8.085 −52.326 −3.136 1.00 108.78 A C ATOM 1836 CB ASN A 234 −8.043 −50.875 −3.626 1.00 108.67 A C ATOM 1837 CG ASN A 234 −6.632 −50.391 −3.902 0.50 108.15 A C ATOM 1838 OD1 ASN A 234 −5.659 −50.948 −3.396 0.50 107.19 A O ATOM 1839 ND2 ASN A 234 −6.517 −49.345 −4.709 0.50 107.96 A N ATOM 1840 C ASN A 234 −9.459 −52.649 −2.528 1.00 108.49 A C ATOM 1841 O ASN A 234 −9.963 −51.911 −1.677 1.00 108.49 A O ATOM 1842 N THR A 235 −10.051 −53.757 −2.959 1.00 107.91 A N ATOM 1843 CA THR A 235 −11.425 −54.102 −2.600 1.00 107.23 A C ATOM 1844 CB THR A 235 −12.174 −54.644 −3.829 1.00 107.20 A C ATOM 1845 OG1 THR A 235 −11.853 −53.843 −4.968 1.00 106.64 A O ATOM 1846 CG2 THR A 235 −13.668 −54.603 −3.617 1.00 107.79 A C ATOM 1847 C THR A 235 −11.435 −55.124 −1.463 1.00 106.91 A C ATOM 1848 O THR A 235 −10.683 −56.093 −1.485 1.00 107.01 A O ATOM 1849 N SER A 236 −12.293 −54.906 −0.476 1.00 106.42 A N ATOM 1850 CA SER A 236 −12.211 −55.631 0.792 1.00 105.96 A C ATOM 1851 CB SER A 236 −12.519 −54.672 1.947 1.00 106.28 A C ATOM 1852 OG SER A 236 −13.001 −55.358 3.088 1.00 107.19 A O ATOM 1853 C SER A 236 −13.113 −56.859 0.866 1.00 105.40 A C ATOM 1854 O SER A 236 −12.858 −57.788 1.636 1.00 105.47 A O ATOM 1855 N VAL A 237 −14.190 −56.852 0.097 1.00 104.60 A N ATOM 1856 CA VAL A 237 −15.082 −58.000 0.073 1.00 103.81 A C ATOM 1857 CB VAL A 237 −16.409 −57.752 0.828 1.00 103.91 A C ATOM 1858 CG1 VAL A 237 −17.148 −59.082 1.053 1.00 103.44 A C ATOM 1859 CG2 VAL A 237 −16.164 −57.036 2.162 1.00 104.04 A C ATOM 1860 C VAL A 237 −15.385 −58.321 −1.371 1.00 103.24 A C ATOM 1861 O VAL A 237 −15.569 −57.421 −2.198 1.00 103.51 A O ATOM 1862 N ILE A 238 −15.424 −59.606 −1.676 1.00 101.99 A N ATOM 1863 CA ILE A 238 −15.684 −60.028 −3.017 1.00 101.00 A C ATOM 1864 CB ILE A 238 −14.373 −60.420 −3.751 1.00 101.07 A C ATOM 1865 CG1 ILE A 238 −13.500 −59.183 −3.978 1.00 100.77 A C ATOM 1866 CD1 ILE A 238 −12.061 −59.496 −4.206 1.00 100.04 A C ATOM 1867 CG2 ILE A 238 −14.668 −61.092 −5.096 1.00 101.02 A C ATOM 1868 C ILE A 238 −16.618 −61.201 −2.948 1.00 100.59 A C ATOM 1869 O ILE A 238 −16.253 −62.259 −2.433 1.00 100.74 A O ATOM 1870 N PHE A 239 −17.838 −60.990 −3.435 1.00 99.82 A N ATOM 1871 CA PHE A 239 −18.724 −62.078 −3.827 1.00 98.86 A C ATOM 1872 CB PHE A 239 −20.172 −61.618 −3.798 1.00 99.15 A C ATOM 1873 CG PHE A 239 −20.797 −61.598 −2.434 1.00 99.85 A C ATOM 1874 CD1 PHE A 239 −20.127 −61.080 −1.340 1.00 100.49 A C ATOM 1875 CE1 PHE A 239 −20.732 −61.043 −0.094 1.00 100.83 A C ATOM 1876 CZ PHE A 239 −22.019 −61.518 0.064 1.00 100.48 A C ATOM 1877 CE2 PHE A 239 −22.703 −62.028 −1.020 1.00 99.75 A C ATOM 1878 CD2 PHE A 239 −22.096 −62.058 −2.261 1.00 100.40 A C ATOM 1879 C PHE A 239 −18.364 −62.402 −5.263 1.00 97.99 A C ATOM 1880 O PHE A 239 −18.073 −61.501 −6.040 1.00 97.23 A O ATOM 1881 N VAL A 240 −18.382 −63.679 −5.620 1.00 97.63 A N ATOM 1882 CA VAL A 240 −18.044 −64.046 −6.977 1.00 97.59 A C ATOM 1883 CB VAL A 240 −16.608 −64.558 −7.094 1.00 97.61 A C ATOM 1884 CG1 VAL A 240 −16.557 −66.055 −6.860 1.00 97.87 A C ATOM 1885 CG2 VAL A 240 −16.042 −64.192 −8.460 1.00 97.17 A C ATOM 1886 C VAL A 240 −19.035 −64.959 −7.693 1.00 97.64 A C ATOM 1887 O VAL A 240 −19.608 −64.563 −8.710 1.00 98.21 A O ATOM 1888 N ASN A 241 −19.250 −66.160 −7.167 1.00 97.27 A N ATOM 1889 CA ASN A 241 −19.978 −67.224 −7.895 1.00 97.51 A C ATOM 1890 CB ASN A 241 −21.473 −66.932 −8.163 1.00 96.79 A C ATOM 1891 CG ASN A 241 −22.260 −68.208 −8.526 1.00 95.57 A C ATOM 1892 OD1 ASN A 241 −21.746 −69.314 −8.410 1.00 94.21 A O ATOM 1893 ND2 ASN A 241 −23.500 −68.050 −8.961 1.00 94.27 A N ATOM 1894 C ASN A 241 −19.281 −67.681 −9.174 1.00 98.24 A C ATOM 1895 O ASN A 241 −19.688 −67.348 −10.294 1.00 98.06 A O ATOM 1896 N ASN A 242 −18.211 −68.440 −8.969 1.00 99.17 A N ATOM 1897 CA ASN A 242 −17.515 −69.136 −10.025 1.00 99.66 A C ATOM 1898 CB ASN A 242 −16.093 −69.473 −9.569 1.00 99.43 A C ATOM 1899 CG ASN A 242 −15.998 −69.808 −8.070 1.00 99.04 A C ATOM 1900 OD1 ASN A 242 −17.002 −69.978 −7.376 1.00 97.86 A O ATOM 1901 ND2 ASN A 242 −14.773 −69.915 −7.578 1.00 98.94 A N ATOM 1902 C ASN A 242 −18.341 −70.376 −10.391 1.00 100.57 A C ATOM 1903 O ASN A 242 −19.414 −70.250 −10.989 1.00 100.63 A O ATOM 1904 N PHE A 243 −17.872 −71.561 −10.016 1.00 101.69 A N ATOM 1905 CA PHE A 243 −18.667 −72.787 −10.145 1.00 102.99 A C ATOM 1906 CB PHE A 243 −20.121 −72.592 −9.669 1.00 103.22 A C ATOM 1907 CG PHE A 243 −20.954 −73.840 −9.768 1.00 105.17 A C ATOM 1908 CD1 PHE A 243 −20.694 −74.937 −8.932 1.00 106.83 A C ATOM 1909 CE1 PHE A 243 −21.444 −76.110 −9.026 1.00 106.94 A C ATOM 1910 CZ PHE A 243 −22.466 −76.193 −9.957 1.00 107.70 A C ATOM 1911 CE2 PHE A 243 −22.736 −75.100 −10.803 1.00 107.37 A C ATOM 1912 CD2 PHE A 243 −21.977 −73.938 −10.705 1.00 106.12 A C ATOM 1913 C PHE A 243 −18.639 −73.365 −11.555 1.00 103.27 A C ATOM 1914 O PHE A 243 −18.285 −74.532 −11.753 1.00 103.68 A O ATOM 1915 N ALA A 244 −19.070 −72.561 −12.517 1.00 103.38 A N ATOM 1916 CA ALA A 244 −18.856 −72.841 −13.917 1.00 103.23 A C ATOM 1917 CB ALA A 244 −20.153 −72.723 −14.690 1.00 103.20 A C ATOM 1918 C ALA A 244 −17.899 −71.754 −14.327 1.00 103.25 A C ATOM 1919 O ALA A 244 −18.327 −70.671 −14.741 1.00 103.62 A O ATOM 1920 N PHE A 245 −16.608 −72.015 −14.158 1.00 103.07 A N ATOM 1921 CA PHE A 245 −15.598 −71.039 −14.540 1.00 103.15 A C ATOM 1922 CB PHE A 245 −15.178 −70.181 −13.339 1.00 103.00 A C ATOM 1923 CG PHE A 245 −15.802 −68.799 −13.327 1.00 102.41 A C ATOM 1924 CD1 PHE A 245 −16.951 −68.519 −14.060 1.00 102.33 A C ATOM 1925 CE1 PHE A 245 −17.528 −67.238 −14.045 1.00 103.08 A C ATOM 1926 CZ PHE A 245 −16.952 −66.226 −13.289 1.00 101.82 A C ATOM 1927 CE2 PHE A 245 −15.815 −66.497 −12.548 1.00 101.84 A C ATOM 1928 CD2 PHE A 245 −15.245 −67.780 −12.568 1.00 102.06 A C ATOM 1929 C PHE A 245 −14.403 −71.630 −15.274 1.00 103.35 A C ATOM 1930 O PHE A 245 −13.838 −70.987 −16.149 1.00 103.36 A O ATOM 1931 N GLY A 246 −14.030 −72.855 −14.939 1.00 103.91 A N ATOM 1932 CA GLY A 246 −12.918 −73.508 −15.609 1.00 104.92 A C ATOM 1933 C GLY A 246 −11.549 −72.876 −15.361 1.00 105.95 A C ATOM 1934 O GLY A 246 −11.396 −71.641 −15.391 1.00 106.04 A O ATOM 1935 N PRO A 247 −10.537 −73.730 −15.139 1.00 106.43 A N ATOM 1936 CA PRO A 247 −9.134 −73.520 −14.827 1.00 107.04 A C ATOM 1937 CB PRO A 247 −8.447 −74.623 −15.635 1.00 107.03 A C ATOM 1938 CG PRO A 247 −9.522 −75.691 −15.846 1.00 106.95 A C ATOM 1939 CD PRO A 247 −10.809 −75.168 −15.268 1.00 106.59 A C ATOM 1940 C PRO A 247 −8.504 −72.161 −15.149 1.00 107.78 A C ATOM 1941 O PRO A 247 −7.877 −71.566 −14.266 1.00 108.03 A O ATOM 1942 N GLU A 248 −8.624 −71.673 −16.379 1.00 108.51 A N ATOM 1943 CA GLU A 248 −7.875 −70.462 −16.732 1.00 109.43 A C ATOM 1944 CB GLU A 248 −7.908 −70.157 −18.241 1.00 109.61 A C ATOM 1945 CG GLU A 248 −6.790 −69.192 −18.684 1.00 109.52 A C ATOM 1946 CD GLU A 248 −6.639 −69.077 −20.186 0.50 109.38 A C ATOM 1947 OE1 GLU A 248 −6.384 −70.105 −20.850 0.50 109.55 A O ATOM 1948 OE2 GLU A 248 −6.753 −67.946 −20.699 0.50 109.25 A O ATOM 1949 C GLU A 248 −8.332 −69.253 −15.909 1.00 109.87 A C ATOM 1950 O GLU A 248 −7.512 −68.592 −15.254 1.00 109.61 A O ATOM 1951 N VAL A 249 −9.640 −68.989 −15.933 1.00 110.47 A N ATOM 1952 CA VAL A 249 −10.215 −67.855 −15.204 1.00 110.84 A C ATOM 1953 CB VAL A 249 −11.745 −67.691 −15.443 1.00 110.79 A C ATOM 1954 CG1 VAL A 249 −12.204 −66.339 −14.946 1.00 110.58 A C ATOM 1955 CG2 VAL A 249 −12.110 −67.849 −16.923 1.00 110.96 A C ATOM 1956 C VAL A 249 −9.941 −68.034 −13.717 1.00 111.09 A C ATOM 1957 O VAL A 249 −9.453 −67.112 −13.059 1.00 111.13 A O ATOM 1958 N ASP A 250 −10.241 −69.239 −13.222 1.00 111.33 A N ATOM 1959 CA ASP A 250 −10.024 −69.658 −11.833 1.00 111.47 A C ATOM 1960 CB ASP A 250 −10.138 −71.176 −11.752 1.00 111.92 A C ATOM 1961 CG ASP A 250 −10.600 −71.661 −10.394 1.00 113.98 A C ATOM 1962 OD1 ASP A 250 −10.206 −71.070 −9.360 1.00 115.46 A O ATOM 1963 OD2 ASP A 250 −11.364 −72.654 −10.369 1.00 116.45 A O ATOM 1964 C ASP A 250 −8.663 −69.235 −11.305 1.00 110.98 A C ATOM 1965 O ASP A 250 −8.560 −68.570 −10.281 1.00 110.69 A O ATOM 1966 N HIS A 251 −7.626 −69.650 −12.021 1.00 110.88 A N ATOM 1967 CA HIS A 251 −6.255 −69.219 −11.785 1.00 110.80 A C ATOM 1968 CB HIS A 251 −5.349 −69.900 −12.822 1.00 110.91 A C ATOM 1969 CG HIS A 251 −3.968 −69.329 −12.919 1.00 110.51 A C ATOM 1970 ND1 HIS A 251 −2.839 −70.112 −12.831 1.00 110.48 A N ATOM 1971 CE1 HIS A 251 −1.768 −69.352 −12.969 1.00 111.11 A C ATOM 1972 NE2 HIS A 251 −2.162 −68.103 −13.146 1.00 110.98 A N ATOM 1973 CD2 HIS A 251 −3.534 −68.063 −13.132 1.00 110.25 A C ATOM 1974 C HIS A 251 −6.152 −67.692 −11.870 1.00 110.65 A C ATOM 1975 O HIS A 251 −5.762 −67.030 −10.909 1.00 110.55 A O ATOM 1976 N GLN A 252 −6.522 −67.137 −13.018 1.00 110.52 A N ATOM 1977 CA GLN A 252 −6.393 −65.705 −13.243 1.00 110.47 A C ATOM 1978 CB GLN A 252 −7.061 −65.296 −14.553 1.00 110.92 A C ATOM 1979 CG GLN A 252 −6.313 −65.695 −15.821 1.00 112.07 A C ATOM 1980 CD GLN A 252 −7.147 −65.437 −17.066 1.00 113.66 A C ATOM 1981 OE1 GLN A 252 −7.908 −66.308 −17.515 1.00 113.98 A O ATOM 1982 NE2 GLN A 252 −7.033 −64.228 −17.613 1.00 113.20 A N ATOM 1983 C GLN A 252 −6.969 −64.889 −12.095 1.00 109.95 A C ATOM 1984 O GLN A 252 −6.453 −63.821 −11.792 1.00 110.05 A O ATOM 1985 N LEU A 253 −8.032 −65.400 −11.467 1.00 109.32 A N ATOM 1986 CA LEU A 253 −8.679 −64.741 −10.325 1.00 108.43 A C ATOM 1987 CB LEU A 253 −9.981 −65.450 −9.960 1.00 108.22 A C ATOM 1988 CG LEU A 253 −11.209 −65.297 −10.852 1.00 107.98 A C ATOM 1989 CD1 LEU A 253 −12.205 −66.389 −10.543 1.00 107.33 A C ATOM 1990 CD2 LEU A 253 −11.866 −63.926 −10.720 1.00 107.70 A C ATOM 1991 C LEU A 253 −7.763 −64.730 −9.112 1.00 108.05 A C ATOM 1992 O LEU A 253 −7.494 −63.676 −8.527 1.00 107.71 A O ATOM 1993 N LYS A 254 −7.286 −65.917 −8.746 1.00 107.72 A N ATOM 1994 CA LYS A 254 −6.353 −66.068 −7.650 1.00 107.63 A C ATOM 1995 CB LYS A 254 −5.772 −67.476 −7.621 1.00 107.29 A C ATOM 1996 CG LYS A 254 −6.791 −68.555 −7.383 1.00 105.91 A C ATOM 1997 CD LYS A 254 −6.310 −69.871 −7.925 1.00 103.89 A C ATOM 1998 CE LYS A 254 −7.397 −70.893 −7.805 1.00 103.55 A C ATOM 1999 NZ LYS A 254 −7.154 −72.105 −8.632 1.00 103.97 A N ATOM 2000 C LYS A 254 −5.238 −65.049 −7.803 1.00 108.18 A C ATOM 2001 O LYS A 254 −4.843 −64.406 −6.832 1.00 108.47 A O ATOM 2002 N GLU A 255 −4.751 −64.875 −9.027 1.00 108.48 A N ATOM 2003 CA GLU A 255 −3.692 −63.908 −9.267 1.00 108.88 A C ATOM 2004 CB GLU A 255 −3.396 −63.757 −10.756 1.00 108.95 A C ATOM 2005 CG GLU A 255 −2.465 −64.839 −11.280 1.00 109.64 A C ATOM 2006 CD GLU A 255 −1.189 −64.277 −11.872 1.00 110.14 A C ATOM 2007 OE1 GLU A 255 −1.124 −63.042 −12.119 1.00 110.31 A O ATOM 2008 OE2 GLU A 255 −0.252 −65.080 −12.080 1.00 109.80 A O ATOM 2009 C GLU A 255 −4.001 −62.557 −8.647 1.00 108.97 A C ATOM 2010 O GLU A 255 −3.157 −61.984 −7.955 1.00 109.15 A O ATOM 2011 N ARG A 256 −5.216 −62.064 −8.873 1.00 108.96 A N ATOM 2012 CA ARG A 256 −5.604 −60.764 −8.351 1.00 108.98 A C ATOM 2013 CB ARG A 256 −6.841 −60.239 −9.057 1.00 109.13 A C ATOM 2014 CG ARG A 256 −6.580 −59.713 −10.441 1.00 109.10 A C ATOM 2015 CD ARG A 256 −6.676 −60.821 −11.428 1.00 108.89 A C ATOM 2016 NE ARG A 256 −6.662 −60.302 −12.778 1.00 110.08 A N ATOM 2017 CZ ARG A 256 −6.262 −60.995 −13.834 1.00 111.25 A C ATOM 2018 NH1 ARG A 256 −5.832 −62.245 −13.705 1.00 111.41 A N ATOM 2019 NH2 ARG A 256 −6.287 −60.427 −15.024 1.00 112.41 A N ATOM 2020 C ARG A 256 −5.851 −60.807 −6.863 1.00 108.93 A C ATOM 2021 O ARG A 256 −5.402 −59.926 −6.141 1.00 108.68 A O ATOM 2022 N PHE A 257 −6.563 −61.839 −6.417 1.00 109.20 A N ATOM 2023 CA PHE A 257 −6.815 −62.051 −4.994 1.00 109.50 A C ATOM 2024 CB PHE A 257 −7.586 −63.345 −4.766 1.00 109.07 A C ATOM 2025 CG PHE A 257 −8.921 −63.389 −5.438 1.00 107.98 A C ATOM 2026 CD1 PHE A 257 −9.706 −62.258 −5.541 1.00 107.26 A C ATOM 2027 CE1 PHE A 257 −10.950 −62.318 −6.170 1.00 107.15 A C ATOM 2028 CZ PHE A 257 −11.419 −63.518 −6.675 1.00 106.38 A C ATOM 2029 CE2 PHE A 257 −10.652 −64.654 −6.558 1.00 106.72 A C ATOM 2030 CD2 PHE A 257 −9.411 −64.587 −5.940 1.00 107.81 A C ATOM 2031 C PHE A 257 −5.516 −62.083 −4.182 1.00 110.15 A C ATOM 2032 O PHE A 257 −5.462 −61.578 −3.054 1.00 110.32 A O ATOM 2033 N ALA A 258 −4.473 −62.672 −4.768 1.00 110.63 A N ATOM 2034 CA ALA A 258 −3.152 −62.733 −4.145 1.00 110.94 A C ATOM 2035 CB ALA A 258 −2.172 −63.467 −5.043 1.00 110.79 A C ATOM 2036 C ALA A 258 −2.625 −61.349 −3.816 1.00 111.19 A C ATOM 2037 O ALA A 258 −1.901 −61.180 −2.843 1.00 111.46 A O ATOM 2038 N ASN A 259 −2.992 −60.366 −4.632 1.00 111.49 A N ATOM 2039 CA ASN A 259 −2.481 −59.012 −4.476 1.00 111.88 A C ATOM 2040 CB ASN A 259 −2.560 −58.251 −5.806 1.00 111.79 A C ATOM 2041 CG ASN A 259 −1.234 −58.216 −6.549 1.00 111.91 A C ATOM 2042 OD1 ASN A 259 −0.601 −59.251 −6.793 1.00 111.54 A O ATOM 2043 ND2 ASN A 259 −0.812 −57.014 −6.926 1.00 111.97 A N ATOM 2044 C ASN A 259 −3.229 −58.250 −3.404 1.00 112.15 A C ATOM 2045 O ASN A 259 −2.871 −57.121 −3.085 1.00 112.24 A O ATOM 2046 N MET A 260 −4.263 −58.880 −2.849 1.00 112.58 A N ATOM 2047 CA MET A 260 −5.232 −58.193 −1.993 1.00 112.90 A C ATOM 2048 CB MET A 260 −6.486 −59.044 −1.812 1.00 112.95 A C ATOM 2049 CG MET A 260 −7.445 −59.000 −2.990 1.00 113.05 A C ATOM 2050 SD MET A 260 −8.920 −59.984 −2.687 1.00 113.36 A S ATOM 2051 CE MET A 260 −9.687 −59.025 −1.382 1.00 111.63 A C ATOM 2052 C MET A 260 −4.689 −57.830 −0.631 1.00 113.06 A C ATOM 2053 O MET A 260 −3.924 −58.588 −0.037 1.00 112.94 A O ATOM 2054 N LYS A 261 −5.110 −56.673 −0.133 1.00 113.38 A N ATOM 2055 CA LYS A 261 −4.741 −56.249 1.206 1.00 113.95 A C ATOM 2056 CB LYS A 261 −5.263 −54.843 1.506 1.00 114.21 A C ATOM 2057 CG LYS A 261 −4.245 −53.722 1.242 1.00 115.28 A C ATOM 2058 CD LYS A 261 −4.332 −53.174 −0.181 1.00 116.47 A C ATOM 2059 CE LYS A 261 −3.575 −51.862 −0.303 1.00 117.59 A C ATOM 2060 NZ LYS A 261 −4.190 −50.945 −1.312 1.00 118.31 A N ATOM 2061 C LYS A 261 −5.220 −57.240 2.262 1.00 113.99 A C ATOM 2062 O LYS A 261 −6.048 −58.115 1.988 1.00 114.41 A O ATOM 2063 N GLU A 262 −4.674 −57.104 3.466 1.00 113.73 A N ATOM 2064 CA GLU A 262 −4.925 −58.032 4.558 1.00 113.21 A C ATOM 2065 CB GLU A 262 −4.130 −57.577 5.791 1.00 113.51 A C ATOM 2066 CG GLU A 262 −3.329 −58.672 6.509 1.00 113.70 A C ATOM 2067 CD GLU A 262 −4.195 −59.618 7.342 1.00 113.53 A C ATOM 2068 OE1 GLU A 262 −3.667 −60.684 7.747 1.00 113.85 A O ATOM 2069 OE2 GLU A 262 −5.386 −59.302 7.587 1.00 111.65 A O ATOM 2070 C GLU A 262 −6.415 −58.090 4.883 1.00 112.63 A C ATOM 2071 O GLU A 262 −7.132 −57.105 4.702 1.00 112.47 A O ATOM 2072 N GLY A 263 −6.875 −59.255 5.329 1.00 112.01 A N ATOM 2073 CA GLY A 263 −8.212 −59.410 5.920 1.00 111.42 A C ATOM 2074 C GLY A 263 −9.468 −59.128 5.098 1.00 110.87 A C ATOM 2075 O GLY A 263 −10.584 −59.164 5.643 1.00 111.04 A O ATOM 2076 N GLY A 264 −9.303 −58.838 3.807 1.00 110.02 A N ATOM 2077 CA GLY A 264 −10.440 −58.710 2.898 1.00 108.89 A C ATOM 2078 C GLY A 264 −11.012 −60.079 2.565 1.00 108.24 A C ATOM 2079 O GLY A 264 −10.278 −60.967 2.148 1.00 108.13 A O ATOM 2080 N ARG A 265 −12.317 −60.264 2.752 1.00 107.57 A N ATOM 2081 CA ARG A 265 −12.914 −61.590 2.543 1.00 106.93 A C ATOM 2082 CB ARG A 265 −14.126 −61.844 3.448 1.00 106.92 A C ATOM 2083 CG ARG A 265 −13.970 −61.538 4.925 1.00 107.03 A C ATOM 2084 CD ARG A 265 −14.658 −60.239 5.291 1.00 106.92 A C ATOM 2085 NE ARG A 265 −13.724 −59.122 5.282 1.00 108.09 A N ATOM 2086 CZ ARG A 265 −14.075 −57.849 5.428 1.00 109.50 A C ATOM 2087 NH1 ARG A 265 −15.352 −57.516 5.579 1.00 110.29 A N ATOM 2088 NH2 ARG A 265 −13.148 −56.902 5.424 1.00 109.90 A N ATOM 2089 C ARG A 265 −13.333 −61.816 1.095 1.00 106.40 A C ATOM 2090 O ARG A 265 −13.480 −60.858 0.325 1.00 106.31 A O ATOM 2091 N ILE A 266 −13.519 −63.092 0.750 1.00 105.47 A N ATOM 2092 CA ILE A 266 −14.006 −63.514 −0.551 1.00 104.83 A C ATOM 2093 CB ILE A 266 −12.905 −64.190 −1.439 1.00 104.80 A C ATOM 2094 CG1 ILE A 266 −11.475 −63.687 −1.138 1.00 104.82 A C ATOM 2095 CD1 ILE A 266 −11.101 −62.325 −1.680 1.00 104.47 A C ATOM 2096 CG2 ILE A 266 −13.306 −64.187 −2.940 1.00 104.09 A C ATOM 2097 C ILE A 266 −15.027 −64.605 −0.308 1.00 104.85 A C ATOM 2098 O ILE A 266 −14.697 −65.648 0.261 1.00 105.00 A O ATOM 2099 N VAL A 267 −16.264 −64.383 −0.749 1.00 104.76 A N ATOM 2100 CA VAL A 267 −17.272 −65.451 −0.763 1.00 104.35 A C ATOM 2101 CB VAL A 267 −18.613 −65.033 −0.125 1.00 104.37 A C ATOM 2102 CG1 VAL A 267 −19.201 −66.199 0.629 1.00 103.94 A C ATOM 2103 CG2 VAL A 267 −18.435 −63.868 0.808 1.00 104.08 A C ATOM 2104 C VAL A 267 −17.511 −65.935 −2.195 1.00 104.20 A C ATOM 2105 O VAL A 267 −17.582 −65.142 −3.127 1.00 103.93 A O ATOM 2106 N SER A 268 −17.649 −67.245 −2.350 1.00 104.26 A N ATOM 2107 CA SER A 268 −17.607 −67.873 −3.651 1.00 104.44 A C ATOM 2108 CB SER A 268 −16.146 −68.082 −4.047 1.00 104.55 A C ATOM 2109 OG SER A 268 −15.540 −69.087 −3.255 1.00 104.04 A O ATOM 2110 C SER A 268 −18.310 −69.222 −3.644 1.00 104.74 A C ATOM 2111 O SER A 268 −18.233 −69.965 −2.667 1.00 104.60 A O ATOM 2112 N SER A 269 −18.973 −69.539 −4.753 1.00 105.26 A N ATOM 2113 CA SER A 269 −19.614 −70.839 −4.938 1.00 105.59 A C ATOM 2114 CB SER A 269 −20.327 −70.902 −6.282 1.00 105.51 A C ATOM 2115 OG SER A 269 −19.484 −70.459 −7.324 1.00 105.14 A O ATOM 2116 C SER A 269 −18.607 −71.970 −4.851 1.00 105.99 A C ATOM 2117 O SER A 269 −18.874 −72.977 −4.198 1.00 106.11 A O ATOM 2118 N LYS A 270 −17.462 −71.790 −5.514 1.00 106.39 A N ATOM 2119 CA LYS A 270 −16.362 −72.754 −5.503 1.00 106.78 A C ATOM 2120 CB LYS A 270 −15.894 −73.047 −6.929 1.00 106.99 A C ATOM 2121 CG LYS A 270 −16.644 −74.158 −7.657 1.00 107.91 A C ATOM 2122 CD LYS A 270 −15.912 −74.531 −8.951 1.00 109.06 A C ATOM 2123 CE LYS A 270 −16.323 −75.902 −9.500 1.00 109.35 A C ATOM 2124 NZ LYS A 270 −15.228 −76.492 −10.339 1.00 109.13 A N ATOM 2125 C LYS A 270 −15.185 −72.220 −4.689 1.00 106.90 A C ATOM 2126 O LYS A 270 −15.010 −71.008 −4.579 1.00 106.68 A O ATOM 2127 N PRO A 271 −14.364 −73.124 −4.120 1.00 107.20 A N ATOM 2128 CA PRO A 271 −13.221 −72.655 −3.348 1.00 107.62 A C ATOM 2129 CB PRO A 271 −13.003 −73.782 −2.334 1.00 107.49 A C ATOM 2130 CG PRO A 271 −13.523 −75.012 −2.996 1.00 106.82 A C ATOM 2131 CD PRO A 271 −14.504 −74.592 −4.063 1.00 107.18 A C ATOM 2132 C PRO A 271 −11.962 −72.428 −4.193 1.00 108.37 A C ATOM 2133 O PRO A 271 −11.557 −73.290 −4.982 1.00 108.36 A O ATOM 2134 N PHE A 272 −11.350 −71.263 −4.018 1.00 109.24 A N ATOM 2135 CA PHE A 272 −10.076 −70.963 −4.653 1.00 110.07 A C ATOM 2136 CB PHE A 272 −9.864 −69.457 −4.717 1.00 110.18 A C ATOM 2137 CG PHE A 272 −10.864 −68.752 −5.574 1.00 110.21 A C ATOM 2138 CD1 PHE A 272 −10.802 −68.847 −6.950 1.00 110.61 A C ATOM 2139 CE1 PHE A 272 −11.727 −68.211 −7.742 1.00 110.94 A C ATOM 2140 CZ PHE A 272 −12.730 −67.465 −7.165 1.00 111.46 A C ATOM 2141 CE2 PHE A 272 −12.810 −67.369 −5.793 1.00 111.56 A C ATOM 2142 CD2 PHE A 272 −11.877 −68.012 −5.005 1.00 111.07 A C ATOM 2143 C PHE A 272 −8.909 −71.644 −3.948 1.00 110.85 A C ATOM 2144 O PHE A 272 −7.866 −71.868 −4.557 1.00 111.20 A O ATOM 2145 N ALA A 273 −9.087 −71.958 −2.666 1.00 111.82 A N ATOM 2146 CA ALA A 273 −8.163 −72.815 −1.918 1.00 112.52 A C ATOM 2147 CB ALA A 273 −7.500 −72.039 −0.817 1.00 112.37 A C ATOM 2148 C ALA A 273 −8.918 −73.998 −1.334 1.00 113.25 A C ATOM 2149 O ALA A 273 −10.091 −73.858 −0.987 1.00 113.34 A O ATOM 2150 N PRO A 274 −8.259 −75.170 −1.236 1.00 114.11 A N ATOM 2151 CA PRO A 274 −8.782 −76.342 −0.513 1.00 114.94 A C ATOM 2152 CB PRO A 274 −7.663 −77.371 −0.685 1.00 114.66 A C ATOM 2153 CG PRO A 274 −7.065 −77.023 −1.985 1.00 114.18 A C ATOM 2154 CD PRO A 274 −7.076 −75.526 −2.040 1.00 114.03 A C ATOM 2155 C PRO A 274 −9.069 −76.123 0.990 1.00 115.88 A C ATOM 2156 O PRO A 274 −8.667 −75.113 1.580 1.00 115.88 A O ATOM 2157 N LEU A 275 −9.763 −77.079 1.595 1.00 117.10 A N ATOM 2158 CA LEU A 275 −10.088 −77.016 3.017 1.00 118.37 A C ATOM 2159 CB LEU A 275 −11.482 −77.602 3.282 1.00 118.36 A C ATOM 2160 CG LEU A 275 −12.669 −76.782 2.763 1.00 117.65 A C ATOM 2161 CD1 LEU A 275 −13.857 −77.672 2.480 1.00 116.90 A C ATOM 2162 CD2 LEU A 275 −13.026 −75.675 3.739 1.00 116.83 A C ATOM 2163 C LEU A 275 −9.038 −77.727 3.857 1.00 119.34 A C ATOM 2164 O LEU A 275 −8.509 −77.149 4.803 1.00 119.32 A O ATOM 2165 N ASN A 276 −8.740 −78.977 3.499 1.00 120.77 A N ATOM 2166 CA ASN A 276 −7.666 −79.742 4.149 1.00 122.27 A C ATOM 2167 CB ASN A 276 −7.823 −81.276 3.931 1.00 122.62 A C ATOM 2168 CG ASN A 276 −7.835 −81.699 2.440 1.00 123.52 A C ATOM 2169 OD1 ASN A 276 −7.195 −81.081 1.586 1.00 124.43 A O ATOM 2170 ND2 ASN A 276 −8.556 −82.782 2.143 1.00 123.75 A N ATOM 2171 C ASN A 276 −6.258 −79.257 3.775 1.00 122.82 A C ATOM 2172 O ASN A 276 −5.400 −80.056 3.386 1.00 122.72 A O ATOM 2173 N PHE A 277 −6.027 −77.951 3.917 1.00 123.71 A N ATOM 2174 CA PHE A 277 −4.778 −77.337 3.472 1.00 124.86 A C ATOM 2175 CB PHE A 277 −5.056 −76.081 2.638 1.00 124.98 A C ATOM 2176 CG PHE A 277 −3.815 −75.448 2.035 1.00 125.69 A C ATOM 2177 CD1 PHE A 277 −3.158 −76.046 0.958 1.00 125.82 A C ATOM 2178 CE1 PHE A 277 −2.025 −75.462 0.395 1.00 125.79 A C ATOM 2179 CZ PHE A 277 −1.539 −74.261 0.897 1.00 126.00 A C ATOM 2180 CE2 PHE A 277 −2.184 −73.648 1.963 1.00 126.13 A C ATOM 2181 CD2 PHE A 277 −3.321 −74.240 2.526 1.00 126.09 A C ATOM 2182 C PHE A 277 −3.808 −77.023 4.606 1.00 125.54 A C ATOM 2183 O PHE A 277 −3.887 −75.958 5.231 1.00 125.72 A O ATOM 2184 N ARG A 278 −2.903 −77.966 4.864 1.00 126.29 A N ATOM 2185 CA ARG A 278 −1.737 −77.727 5.706 1.00 126.93 A C ATOM 2186 CB ARG A 278 −1.410 −78.951 6.574 1.00 127.33 A C ATOM 2187 CG ARG A 278 −0.092 −78.803 7.350 1.00 129.03 A C ATOM 2188 CD ARG A 278 0.240 −79.993 8.237 1.00 130.93 A C ATOM 2189 NE ARG A 278 1.357 −79.662 9.124 1.00 132.79 A N ATOM 2190 CZ ARG A 278 1.716 −80.363 10.200 1.00 133.78 A C ATOM 2191 NH1 ARG A 278 1.048 −81.460 10.548 1.00 134.11 A N ATOM 2192 NH2 ARG A 278 2.749 −79.962 10.934 1.00 133.73 A N ATOM 2193 C ARG A 278 −0.568 −77.386 4.785 1.00 126.83 A C ATOM 2194 O ARG A 278 −0.299 −78.103 3.819 1.00 127.02 A O ATOM 2195 N ILE A 279 0.115 −76.288 5.085 1.00 126.77 A N ATOM 2196 CA ILE A 279 1.178 −75.768 4.224 1.00 126.81 A C ATOM 2197 CB ILE A 279 1.410 −74.248 4.474 1.00 126.66 A C ATOM 2198 CG1 ILE A 279 2.498 −73.694 3.555 1.00 126.38 A C ATOM 2199 CD1 ILE A 279 2.496 −72.187 3.461 1.00 126.72 A C ATOM 2200 CG2 ILE A 279 1.688 −73.960 5.957 1.00 126.34 A C ATOM 2201 C ILE A 279 2.463 −76.573 4.400 1.00 127.10 A C ATOM 2202 O ILE A 279 2.790 −76.980 5.518 1.00 127.34 A O ATOM 2203 N ASN A 280 3.167 −76.826 3.293 1.00 127.21 A N ATOM 2204 CA ASN A 280 4.412 −77.608 3.310 1.00 127.25 A C ATOM 2205 CB ASN A 280 4.213 −78.984 3.986 1.00 127.47 A C ATOM 2206 CG ASN A 280 2.819 −79.580 3.740 1.00 128.10 A C ATOM 2207 OD1 ASN A 280 2.404 −79.779 2.597 1.00 129.09 A O ATOM 2208 ND2 ASN A 280 2.096 −79.861 4.823 1.00 128.28 A N ATOM 2209 C ASN A 280 5.072 −77.797 1.947 1.00 127.06 A C ATOM 2210 O ASN A 280 4.403 −78.102 0.957 1.00 126.98 A O ATOM 2211 N SER A 281 6.394 −77.615 1.925 1.00 126.94 A N ATOM 2212 CA SER A 281 7.261 −77.989 0.795 1.00 126.75 A C ATOM 2213 CB SER A 281 7.322 −79.522 0.629 1.00 126.86 A C ATOM 2214 OG SER A 281 7.696 −80.182 1.832 1.00 127.14 A O ATOM 2215 C SER A 281 6.903 −77.312 −0.538 1.00 126.49 A C ATOM 2216 O SER A 281 7.233 −76.144 −0.751 1.00 126.39 A O ATOM 2217 N ARG A 282 6.220 −78.059 −1.412 1.00 126.17 A N ATOM 2218 CA ARG A 282 5.963 −77.654 −2.803 1.00 125.69 A C ATOM 2219 CB ARG A 282 6.149 −78.848 −3.762 1.00 125.91 A C ATOM 2220 CG ARG A 282 7.526 −79.538 −3.699 1.00 126.51 A C ATOM 2221 CD ARG A 282 8.123 −79.751 −5.103 1.00 127.19 A C ATOM 2222 NE ARG A 282 7.630 −80.955 −5.778 1.00 126.98 A N ATOM 2223 CZ ARG A 282 8.405 −81.938 −6.237 1.00 126.97 A C ATOM 2224 NH1 ARG A 282 9.728 −81.879 −6.109 1.00 126.64 A N ATOM 2225 NH2 ARG A 282 7.853 −82.984 −6.835 1.00 126.83 A N ATOM 2226 C ARG A 282 4.583 −77.015 −3.024 1.00 125.16 A C ATOM 2227 O ARG A 282 4.027 −77.084 −4.130 1.00 125.20 A O ATOM 2228 N ASN A 283 4.044 −76.387 −1.978 1.00 124.36 A N ATOM 2229 CA ASN A 283 2.733 −75.736 −2.058 1.00 123.38 A C ATOM 2230 CB ASN A 283 1.650 −76.572 −1.343 1.00 123.52 A C ATOM 2231 CG ASN A 283 1.763 −76.531 0.192 1.00 123.93 A C ATOM 2232 OD1 ASN A 283 2.633 −75.861 0.765 1.00 124.69 A O ATOM 2233 ND2 ASN A 283 0.872 −77.254 0.857 1.00 123.45 A N ATOM 2234 C ASN A 283 2.724 −74.293 −1.556 1.00 122.54 A C ATOM 2235 O ASN A 283 1.655 −73.712 −1.361 1.00 122.71 A O ATOM 2236 N LEU A 284 3.905 −73.714 −1.345 1.00 121.30 A N ATOM 2237 CA LEU A 284 3.991 −72.316 −0.902 1.00 120.23 A C ATOM 2238 CB LEU A 284 5.308 −72.019 −0.174 1.00 120.38 A C ATOM 2239 CG LEU A 284 6.219 −73.117 0.389 1.00 120.53 A C ATOM 2240 CD1 LEU A 284 7.386 −72.454 1.097 1.00 120.04 A C ATOM 2241 CD2 LEU A 284 5.499 −74.116 1.313 1.00 121.01 A C ATOM 2242 C LEU A 284 3.811 −71.379 −2.094 1.00 119.34 A C ATOM 2243 O LEU A 284 3.693 −70.162 −1.941 1.00 119.18 A O ATOM 2244 N SER A 285 3.811 −71.976 −3.282 1.00 118.34 A N ATOM 2245 CA SER A 285 3.418 −71.322 −4.525 1.00 117.26 A C ATOM 2246 CB SER A 285 3.626 −72.296 −5.683 1.00 117.36 A C ATOM 2247 OG SER A 285 3.130 −73.598 −5.374 1.00 116.48 A O ATOM 2248 C SER A 285 1.949 −70.898 −4.511 1.00 116.61 A C ATOM 2249 O SER A 285 1.598 −69.850 −5.069 1.00 116.53 A O ATOM 2250 N ASP A 286 1.119 −71.719 −3.856 1.00 115.46 A N ATOM 2251 CA ASP A 286 −0.343 −71.666 −3.923 1.00 114.40 A C ATOM 2252 CB ASP A 286 −0.931 −72.901 −3.253 1.00 114.37 A C ATOM 2253 CG ASP A 286 −0.467 −74.181 −3.891 1.00 114.39 A C ATOM 2254 OD1 ASP A 286 0.662 −74.214 −4.419 1.00 115.99 A O ATOM 2255 OD2 ASP A 286 −1.226 −75.162 −3.863 1.00 113.96 A O ATOM 2256 C ASP A 286 −0.973 −70.447 −3.292 1.00 113.73 A C ATOM 2257 O ASP A 286 −0.418 −69.860 −2.374 1.00 113.64 A O ATOM 2258 N ILE A 287 −2.153 −70.091 −3.788 1.00 113.03 A N ATOM 2259 CA ILE A 287 −2.944 −68.989 −3.241 1.00 112.50 A C ATOM 2260 CB ILE A 287 −4.243 −68.727 −4.095 1.00 112.53 A C ATOM 2261 CG1 ILE A 287 −5.004 −67.491 −3.614 1.00 112.14 A C ATOM 2262 CD1 ILE A 287 −4.324 −66.201 −3.902 1.00 112.17 A C ATOM 2263 CG2 ILE A 287 −5.183 −69.940 −4.097 1.00 112.69 A C ATOM 2264 C ILE A 287 −3.284 −69.213 −1.763 1.00 112.05 A C ATOM 2265 O ILE A 287 −3.176 −68.298 −0.944 1.00 111.77 A O ATOM 2266 N GLY A 288 −3.655 −70.446 −1.433 1.00 111.65 A N ATOM 2267 CA GLY A 288 −4.117 −70.791 −0.097 1.00 111.42 A C ATOM 2268 C GLY A 288 −3.144 −70.596 1.049 1.00 111.18 A C ATOM 2269 O GLY A 288 −3.483 −70.836 2.199 1.00 111.17 A O ATOM 2270 N THR A 289 −1.932 −70.163 0.745 1.00 111.16 A N ATOM 2271 CA THR A 289 −0.940 −69.935 1.781 1.00 111.06 A C ATOM 2272 CB THR A 289 0.478 −69.814 1.191 1.00 110.93 A C ATOM 2273 OG1 THR A 289 0.571 −68.624 0.403 1.00 110.66 A O ATOM 2274 CG2 THR A 289 0.788 −71.013 0.318 1.00 110.68 A C ATOM 2275 C THR A 289 −1.289 −68.676 2.568 1.00 111.19 A C ATOM 2276 O THR A 289 −0.880 −68.523 3.721 1.00 111.04 A O ATOM 2277 N ILE A 290 −2.060 −67.789 1.939 1.00 111.39 A N ATOM 2278 CA ILE A 290 −2.389 −66.487 2.528 1.00 111.58 A C ATOM 2279 CB ILE A 290 −1.880 −65.310 1.654 1.00 111.58 A C ATOM 2280 CG1 ILE A 290 −2.455 −65.389 0.233 1.00 111.41 A C ATOM 2281 CD1 ILE A 290 −2.664 −64.031 −0.417 1.00 111.16 A C ATOM 2282 CG2 ILE A 290 −0.356 −65.289 1.622 1.00 112.15 A C ATOM 2283 C ILE A 290 −3.874 −66.275 2.806 1.00 111.55 A C ATOM 2284 O ILE A 290 −4.367 −65.160 2.674 1.00 111.58 A O ATOM 2285 N MET A 291 −4.584 −67.329 3.194 1.00 111.76 A N ATOM 2286 CA MET A 291 −6.002 −67.192 3.490 1.00 112.15 A C ATOM 2287 CB MET A 291 −6.803 −66.950 2.213 1.00 112.16 A C ATOM 2288 CG MET A 291 −6.823 −68.099 1.224 1.00 111.43 A C ATOM 2289 SD MET A 291 −8.046 −67.796 −0.062 1.00 110.98 A S ATOM 2290 CE MET A 291 −7.503 −66.241 −0.775 1.00 108.38 A C ATOM 2291 C MET A 291 −6.630 −68.340 4.259 1.00 112.75 A C ATOM 2292 O MET A 291 −6.300 −69.501 4.039 1.00 112.78 A O ATOM 2293 N ARG A 292 −7.540 −67.983 5.162 1.00 113.41 A N ATOM 2294 CA ARG A 292 −8.398 −68.933 5.842 1.00 114.12 A C ATOM 2295 CB ARG A 292 −8.993 −68.291 7.084 1.00 114.22 A C ATOM 2296 CG ARG A 292 −8.460 −68.779 8.407 1.00 114.69 A C ATOM 2297 CD ARG A 292 −9.207 −68.065 9.530 1.00 115.78 A C ATOM 2298 NE ARG A 292 −9.079 −66.610 9.408 1.00 116.24 A N ATOM 2299 CZ ARG A 292 −9.924 −65.722 9.925 1.00 116.72 A C ATOM 2300 NH1 ARG A 292 −10.994 −66.115 10.609 1.00 117.49 A N ATOM 2301 NH2 ARG A 292 −9.703 −64.428 9.747 1.00 116.79 A N ATOM 2302 C ARG A 292 −9.531 −69.249 4.900 1.00 114.61 A C ATOM 2303 O ARG A 292 −10.054 −68.347 4.255 1.00 114.90 A O ATOM 2304 N VAL A 293 −9.916 −70.518 4.818 1.00 115.18 A N ATOM 2305 CA VAL A 293 −11.056 −70.918 3.999 1.00 115.88 A C ATOM 2306 CB VAL A 293 −10.631 −71.731 2.756 1.00 115.75 A C ATOM 2307 CG1 VAL A 293 −11.817 −71.978 1.832 1.00 115.27 A C ATOM 2308 CG2 VAL A 293 −9.531 −71.009 2.005 1.00 116.00 A C ATOM 2309 C VAL A 293 −12.012 −71.731 4.856 1.00 116.64 A C ATOM 2310 O VAL A 293 −11.636 −72.751 5.425 1.00 116.87 A O ATOM 2311 N VAL A 294 −13.249 −71.263 4.951 1.00 117.53 A N ATOM 2312 CA VAL A 294 −14.262 −71.906 5.779 1.00 118.26 A C ATOM 2313 CB VAL A 294 −14.502 −71.091 7.103 1.00 118.22 A C ATOM 2314 CG1 VAL A 294 −13.912 −69.678 7.016 1.00 118.10 A C ATOM 2315 CG2 VAL A 294 −15.967 −71.042 7.500 1.00 118.33 A C ATOM 2316 C VAL A 294 −15.537 −72.146 4.959 1.00 118.92 A C ATOM 2317 O VAL A 294 −15.997 −71.245 4.256 1.00 119.08 A O ATOM 2318 N GLU A 295 −16.071 −73.371 5.019 1.00 119.80 A N ATOM 2319 CA GLU A 295 −17.357 −73.716 4.398 1.00 120.84 A C ATOM 2320 CB GLU A 295 −17.745 −75.188 4.625 1.00 120.76 A C ATOM 2321 CG GLU A 295 −16.667 −76.247 4.427 1.00 120.38 A C ATOM 2322 CD GLU A 295 −16.858 −77.469 5.325 1.00 118.91 A C ATOM 2323 OE1 GLU A 295 −16.632 −77.357 6.550 1.00 117.49 A O ATOM 2324 OE2 GLU A 295 −17.218 −78.545 4.800 1.00 119.03 A O ATOM 2325 C GLU A 295 −18.441 −72.878 5.056 1.00 121.92 A C ATOM 2326 O GLU A 295 −18.289 −72.443 6.202 1.00 122.06 A O ATOM 2327 N LEU A 296 −19.543 −72.666 4.345 1.00 123.02 A N ATOM 2328 CA LEU A 296 −20.689 −71.985 4.922 1.00 123.95 A C ATOM 2329 CB LEU A 296 −20.870 −70.584 4.334 1.00 123.92 A C ATOM 2330 CG LEU A 296 −19.812 −69.540 4.724 1.00 124.04 A C ATOM 2331 CD1 LEU A 296 −20.104 −68.189 4.102 1.00 123.49 A C ATOM 2332 CD2 LEU A 296 −19.698 −69.399 6.238 1.00 125.01 A C ATOM 2333 C LEU A 296 −21.930 −72.821 4.740 1.00 124.81 A C ATOM 2334 O LEU A 296 −22.099 −73.495 3.717 1.00 124.82 A O ATOM 2335 N SER A 297 −22.779 −72.782 5.761 1.00 126.02 A N ATOM 2336 CA SER A 297 −24.003 −73.572 5.807 1.00 127.25 A C ATOM 2337 CB SER A 297 −24.463 −73.724 7.253 1.00 127.13 A C ATOM 2338 OG SER A 297 −23.407 −74.194 8.074 1.00 127.28 A O ATOM 2339 C SER A 297 −25.092 −72.906 4.968 1.00 128.15 A C ATOM 2340 O SER A 297 −25.291 −71.691 5.066 1.00 128.32 A O ATOM 2341 N PRO A 298 −25.800 −73.694 4.139 1.00 128.94 A N ATOM 2342 CA PRO A 298 −26.773 −73.100 3.211 1.00 129.74 A C ATOM 2343 CB PRO A 298 −26.762 −74.084 2.037 1.00 129.72 A C ATOM 2344 CG PRO A 298 −26.352 −75.416 2.652 1.00 129.26 A C ATOM 2345 CD PRO A 298 −25.701 −75.158 3.986 1.00 128.74 A C ATOM 2346 C PRO A 298 −28.199 −72.939 3.779 1.00 130.60 A C ATOM 2347 O PRO A 298 −28.521 −73.506 4.833 1.00 130.62 A O ATOM 2348 N LEU A 299 −29.037 −72.159 3.088 1.00 131.59 A N ATOM 2349 CA LEU A 299 −30.481 −72.139 3.370 1.00 132.52 A C ATOM 2350 CB LEU A 299 −31.151 −70.850 2.863 1.00 132.21 A C ATOM 2351 CG LEU A 299 −31.246 −69.571 3.716 1.00 132.15 A C ATOM 2352 CD1 LEU A 299 −31.642 −69.840 5.167 1.00 131.79 A C ATOM 2353 CD2 LEU A 299 −29.961 −68.760 3.667 1.00 132.58 A C ATOM 2354 C LEU A 299 −31.146 −73.367 2.746 1.00 133.36 A C ATOM 2355 O LEU A 299 −30.573 −74.463 2.746 1.00 133.49 A O ATOM 2356 N LYS A 300 −32.357 −73.188 2.226 1.00 134.44 A N ATOM 2357 CA LYS A 300 −33.057 −74.260 1.516 1.00 135.47 A C ATOM 2358 CB LYS A 300 −34.149 −74.888 2.399 1.00 135.37 A C ATOM 2359 CG LYS A 300 −34.020 −74.645 3.907 1.00 135.09 A C ATOM 2360 CD LYS A 300 −33.073 −75.607 4.589 1.00 134.40 A C ATOM 2361 CE LYS A 300 −32.671 −75.038 5.928 1.00 134.47 A C ATOM 2362 NZ LYS A 300 −31.198 −75.066 6.110 1.00 134.51 A N ATOM 2363 C LYS A 300 −33.654 −73.737 0.197 1.00 136.28 A C ATOM 2364 O LYS A 300 −34.594 −74.322 −0.350 1.00 136.32 A O ATOM 2365 N GLY A 301 −33.098 −72.631 −0.302 1.00 137.14 A N ATOM 2366 CA GLY A 301 −33.564 −72.006 −1.538 1.00 138.22 A C ATOM 2367 C GLY A 301 −32.778 −72.425 −2.773 1.00 139.08 A C ATOM 2368 O GLY A 301 −33.117 −72.035 −3.898 1.00 139.24 A O ATOM 2369 N SER A 302 −31.727 −73.221 −2.568 1.00 139.63 A N ATOM 2370 CA SER A 302 −30.875 −73.683 −3.664 1.00 140.06 A C ATOM 2371 CB SER A 302 −29.608 −74.353 −3.116 1.00 140.19 A C ATOM 2372 OG SER A 302 −28.788 −73.422 −2.421 1.00 140.01 A O ATOM 2373 C SER A 302 −31.633 −74.621 −4.610 1.00 140.31 A C ATOM 2374 O SER A 302 −31.893 −75.781 −4.276 1.00 140.17 A O ATOM 2375 N VAL A 303 −31.975 −74.092 −5.787 1.00 140.76 A N ATOM 2376 CA VAL A 303 −32.798 −74.790 −6.794 1.00 141.09 A C ATOM 2377 CB VAL A 303 −33.786 −73.786 −7.504 1.00 141.05 A C ATOM 2378 CG1 VAL A 303 −33.040 −72.857 −8.450 1.00 141.07 A C ATOM 2379 CG2 VAL A 303 −34.944 −74.512 −8.214 1.00 140.76 A C ATOM 2380 C VAL A 303 −31.957 −75.614 −7.806 1.00 141.33 A C ATOM 2381 O VAL A 303 −32.494 −76.187 −8.763 1.00 141.46 A O ATOM 2382 N SER A 304 −30.642 −75.669 −7.576 1.00 141.52 A N ATOM 2383 CA SER A 304 −29.724 −76.537 −8.340 1.00 141.55 A C ATOM 2384 CB SER A 304 −28.263 −76.277 −7.933 1.00 141.59 A C ATOM 2385 OG SER A 304 −28.160 −75.759 −6.613 1.00 141.11 A O ATOM 2386 C SER A 304 −30.085 −78.033 −8.218 1.00 141.57 A C ATOM 2387 O SER A 304 −30.584 −78.471 −7.176 1.00 141.59 A O ATOM 2388 N TRP A 305 −29.830 −78.796 −9.288 1.00 141.53 A N ATOM 2389 CA TRP A 305 −30.328 −80.189 −9.465 1.00 141.37 A C ATOM 2390 CB TRP A 305 −29.330 −81.232 −8.952 1.00 141.57 A C ATOM 2391 CG TRP A 305 −27.936 −81.029 −9.404 1.00 142.85 A C ATOM 2392 CD1 TRP A 305 −27.382 −81.474 −10.566 1.00 143.75 A C ATOM 2393 NE1 TRP A 305 −26.057 −81.104 −10.631 1.00 144.75 A N ATOM 2394 CE2 TRP A 305 −25.733 −80.404 −9.498 1.00 145.21 A C ATOM 2395 CD2 TRP A 305 −26.897 −80.341 −8.695 1.00 144.52 A C ATOM 2396 CE3 TRP A 305 −26.835 −79.673 −7.462 1.00 144.74 A C ATOM 2397 CZ3 TRP A 305 −25.627 −79.096 −7.074 1.00 145.23 A C ATOM 2398 CH2 TRP A 305 −24.483 −79.171 −7.896 1.00 145.43 A C ATOM 2399 CZ2 TRP A 305 −24.515 −79.820 −9.107 1.00 145.64 A C ATOM 2400 C TRP A 305 −31.716 −80.445 −8.853 1.00 140.79 A C ATOM 2401 O TRP A 305 −31.997 −81.543 −8.351 1.00 140.57 A O ATOM 2402 N THR A 306 −32.567 −79.417 −8.915 1.00 140.15 A N ATOM 2403 CA THR A 306 −33.928 −79.422 −8.353 1.00 139.43 A C ATOM 2404 CB THR A 306 −34.857 −80.505 −9.029 1.00 139.57 A C ATOM 2405 OG1 THR A 306 −34.249 −81.804 −8.961 1.00 138.88 A O ATOM 2406 CG2 THR A 306 −35.123 −80.144 −10.493 1.00 139.19 A C ATOM 2407 C THR A 306 −33.975 −79.433 −6.798 1.00 138.86 A C ATOM 2408 O THR A 306 −34.821 −80.098 −6.175 1.00 138.75 A O ATOM 2409 N GLY A 307 −33.072 −78.669 −6.183 1.00 137.97 A N ATOM 2410 CA GLY A 307 −33.010 −78.564 −4.721 1.00 136.97 A C ATOM 2411 C GLY A 307 −31.772 −79.152 −4.051 1.00 136.09 A C ATOM 2412 O GLY A 307 −31.526 −78.884 −2.874 1.00 136.13 A O ATOM 2413 N LYS A 308 −31.003 −79.941 −4.809 1.00 134.96 A N ATOM 2414 CA LYS A 308 −29.826 −80.692 −4.334 1.00 133.92 A C ATOM 2415 CB LYS A 308 −29.079 −81.293 −5.534 1.00 133.96 A C ATOM 2416 CG LYS A 308 −29.038 −82.818 −5.596 1.00 134.24 A C ATOM 2417 CD LYS A 308 −30.411 −83.448 −5.790 1.00 133.99 A C ATOM 2418 CE LYS A 308 −30.337 −84.953 −5.587 1.00 133.51 A C ATOM 2419 NZ LYS A 308 −31.660 −85.592 −5.805 1.00 133.21 A N ATOM 2420 C LYS A 308 −28.806 −79.962 −3.432 1.00 133.13 A C ATOM 2421 O LYS A 308 −28.616 −78.742 −3.552 1.00 133.33 A O ATOM 2422 N PRO A 309 −28.151 −80.720 −2.522 1.00 132.02 A N ATOM 2423 CA PRO A 309 −27.011 −80.289 −1.698 1.00 130.88 A C ATOM 2424 CB PRO A 309 −26.411 −81.628 −1.208 1.00 131.12 A C ATOM 2425 CG PRO A 309 −27.354 −82.744 −1.745 1.00 131.67 A C ATOM 2426 CD PRO A 309 −28.630 −82.045 −2.083 1.00 131.91 A C ATOM 2427 C PRO A 309 −25.920 −79.470 −2.411 1.00 129.52 A C ATOM 2428 O PRO A 309 −25.245 −79.976 −3.320 1.00 129.59 A O ATOM 2429 N VAL A 310 −25.772 −78.211 −1.992 1.00 127.65 A N ATOM 2430 CA VAL A 310 −24.582 −77.389 −2.285 1.00 125.53 A C ATOM 2431 CB VAL A 310 −24.842 −76.267 −3.336 1.00 125.64 A C ATOM 2432 CG1 VAL A 310 −24.954 −76.843 −4.731 1.00 125.70 A C ATOM 2433 CG2 VAL A 310 −26.070 −75.436 −2.978 1.00 125.70 A C ATOM 2434 C VAL A 310 −24.062 −76.758 −0.990 1.00 123.84 A C ATOM 2435 O VAL A 310 −24.697 −76.884 0.058 1.00 123.86 A O ATOM 2436 N SER A 311 −22.910 −76.092 −1.066 1.00 121.54 A N ATOM 2437 CA SER A 311 −22.316 −75.390 0.076 1.00 119.36 A C ATOM 2438 CB SER A 311 −21.397 −76.326 0.863 1.00 119.51 A C ATOM 2439 OG SER A 311 −22.089 −77.486 1.292 1.00 119.01 A O ATOM 2440 C SER A 311 −21.535 −74.174 −0.420 1.00 117.87 A C ATOM 2441 O SER A 311 −21.243 −74.076 −1.615 1.00 117.96 A O ATOM 2442 N TYR A 312 −21.198 −73.250 0.479 1.00 115.69 A N ATOM 2443 CA TYR A 312 −20.486 −72.029 0.075 1.00 113.79 A C ATOM 2444 CB TYR A 312 −21.440 −70.830 0.034 1.00 113.95 A C ATOM 2445 CG TYR A 312 −22.589 −71.079 −0.915 1.00 114.45 A C ATOM 2446 CD1 TYR A 312 −22.454 −70.835 −2.277 1.00 114.96 A C ATOM 2447 CE1 TYR A 312 −23.496 −71.086 −3.158 1.00 114.97 A C ATOM 2448 CZ TYR A 312 −24.681 −71.597 −2.682 1.00 115.11 A C ATOM 2449 OH TYR A 312 −25.703 −71.837 −3.560 1.00 116.33 A O ATOM 2450 CE2 TYR A 312 −24.846 −71.863 −1.335 1.00 115.35 A C ATOM 2451 CD2 TYR A 312 −23.799 −71.609 −0.459 1.00 115.34 A C ATOM 2452 C TYR A 312 −19.230 −71.776 0.907 1.00 112.26 A C ATOM 2453 O TYR A 312 −18.986 −72.492 1.870 1.00 112.27 A O ATOM 2454 N TYR A 313 −18.427 −70.783 0.519 1.00 110.19 A N ATOM 2455 CA TYR A 313 −17.052 −70.674 1.004 1.00 108.18 A C ATOM 2456 CB TYR A 313 −16.108 −71.326 −0.001 1.00 107.76 A C ATOM 2457 CG TYR A 313 −16.416 −72.778 −0.256 1.00 106.26 A C ATOM 2458 CD1 TYR A 313 −15.920 −73.766 0.580 1.00 105.49 A C ATOM 2459 CE1 TYR A 313 −16.199 −75.098 0.352 1.00 105.51 A C ATOM 2460 CZ TYR A 313 −16.994 −75.456 −0.720 1.00 105.15 A C ATOM 2461 OH TYR A 313 −17.279 −76.781 −0.941 1.00 105.20 A O ATOM 2462 CE2 TYR A 313 −17.500 −74.494 −1.564 1.00 104.97 A C ATOM 2463 CD2 TYR A 313 −17.209 −73.162 −1.328 1.00 105.35 A C ATOM 2464 C TYR A 313 −16.584 −69.258 1.289 1.00 107.55 A C ATOM 2465 O TYR A 313 −16.663 −68.384 0.437 1.00 107.42 A O ATOM 2466 N LEU A 314 −16.068 −69.037 2.489 1.00 106.83 A N ATOM 2467 CA LEU A 314 −15.602 −67.710 2.863 1.00 106.32 A C ATOM 2468 CB LEU A 314 −16.351 −67.204 4.105 1.00 106.10 A C ATOM 2469 CG LEU A 314 −15.674 −66.194 5.037 1.00 105.66 A C ATOM 2470 CD1 LEU A 314 −15.310 −64.912 4.332 1.00 105.20 A C ATOM 2471 CD2 LEU A 314 −16.559 −65.908 6.223 1.00 105.51 A C ATOM 2472 C LEU A 314 −14.078 −67.654 3.036 1.00 106.10 A C ATOM 2473 O LEU A 314 −13.517 −68.217 3.975 1.00 106.33 A O ATOM 2474 N HIS A 315 −13.418 −66.976 2.108 1.00 105.77 A N ATOM 2475 CA HIS A 315 −11.980 −66.846 2.141 1.00 105.38 A C ATOM 2476 CB HIS A 315 −11.390 −66.844 0.734 1.00 104.88 A C ATOM 2477 CG HIS A 315 −11.887 −67.943 −0.153 1.00 103.08 A C ATOM 2478 ND1 HIS A 315 −12.941 −67.778 −1.022 1.00 101.22 A N ATOM 2479 CE1 HIS A 315 −13.142 −68.901 −1.687 1.00 100.76 A C ATOM 2480 NE2 HIS A 315 −12.249 −69.786 −1.287 1.00 100.83 A N ATOM 2481 CD2 HIS A 315 −11.447 −69.209 −0.335 1.00 101.73 A C ATOM 2482 C HIS A 315 −11.650 −65.529 2.801 1.00 106.02 A C ATOM 2483 O HIS A 315 −11.980 −64.471 2.266 1.00 106.12 A O ATOM 2484 N THR A 316 −11.013 −65.590 3.968 1.00 106.77 A N ATOM 2485 CA THR A 316 −10.501 −64.387 4.628 1.00 107.28 A C ATOM 2486 CB THR A 316 −10.833 −64.352 6.142 1.00 107.10 A C ATOM 2487 OG1 THR A 316 −11.948 −65.207 6.427 1.00 107.47 A O ATOM 2488 CG2 THR A 316 −11.152 −62.941 6.591 1.00 106.54 A C ATOM 2489 C THR A 316 −8.995 −64.391 4.444 1.00 107.83 A C ATOM 2490 O THR A 316 −8.346 −65.394 4.738 1.00 107.85 A O ATOM 2491 N ILE A 317 −8.450 −63.286 3.935 1.00 108.68 A N ATOM 2492 CA ILE A 317 −7.002 −63.138 3.728 1.00 109.53 A C ATOM 2493 CB ILE A 317 −6.646 −61.827 2.930 1.00 109.36 A C ATOM 2494 CG1 ILE A 317 −7.082 −61.913 1.460 1.00 108.76 A C ATOM 2495 CD1 ILE A 317 −6.416 −62.990 0.648 1.00 107.83 A C ATOM 2496 CG2 ILE A 317 −5.165 −61.473 3.039 1.00 109.13 A C ATOM 2497 C ILE A 317 −6.282 −63.138 5.073 1.00 110.50 A C ATOM 2498 O ILE A 317 −6.424 −62.205 5.863 1.00 110.77 A O ATOM 2499 N ASP A 318 −5.537 −64.204 5.342 1.00 111.78 A N ATOM 2500 CA ASP A 318 −4.662 −64.238 6.507 1.00 113.00 A C ATOM 2501 CB ASP A 318 −5.169 −65.224 7.569 1.00 113.04 A C ATOM 2502 CG ASP A 318 −4.698 −64.862 8.990 1.00 113.30 A C ATOM 2503 OD1 ASP A 318 −4.359 −63.679 9.249 1.00 112.20 A O ATOM 2504 OD2 ASP A 318 −4.677 −65.771 9.851 1.00 113.57 A O ATOM 2505 C ASP A 318 −3.218 −64.537 6.102 1.00 113.74 A C ATOM 2506 O ASP A 318 −2.819 −65.698 5.955 1.00 113.50 A O ATOM 2507 N ARG A 319 −2.448 −63.466 5.916 1.00 114.82 A N ATOM 2508 CA ARG A 319 −1.025 −63.569 5.592 1.00 116.06 A C ATOM 2509 CB ARG A 319 −0.505 −62.242 5.024 1.00 116.22 A C ATOM 2510 CG ARG A 319 −0.350 −62.278 3.513 1.00 116.72 A C ATOM 2511 CD ARG A 319 −0.663 −60.954 2.854 1.00 117.45 A C ATOM 2512 NE ARG A 319 −1.286 −61.187 1.553 1.00 118.04 A N ATOM 2513 CZ ARG A 319 −1.598 −60.244 0.670 1.00 118.36 A C ATOM 2514 NH1 ARG A 319 −1.348 −58.964 0.915 1.00 118.65 A N ATOM 2515 NH2 ARG A 319 −2.172 −60.588 −0.470 1.00 118.99 A N ATOM 2516 C ARG A 319 −0.180 −64.033 6.782 1.00 116.65 A C ATOM 2517 O ARG A 319 1.042 −63.842 6.803 1.00 116.54 A O ATOM 2518 N THR A 320 −0.854 −64.655 7.753 1.00 117.47 A N ATOM 2519 CA THR A 320 −0.242 −65.146 8.985 1.00 117.98 A C ATOM 2520 CB THR A 320 −1.145 −64.875 10.202 1.00 117.87 A C ATOM 2521 OG1 THR A 320 −0.943 −63.524 10.626 1.00 117.55 A O ATOM 2522 CG2 THR A 320 −0.832 −65.816 11.364 1.00 117.83 A C ATOM 2523 C THR A 320 0.111 −66.617 8.874 1.00 118.52 A C ATOM 2524 O THR A 320 1.154 −67.028 9.369 1.00 118.75 A O ATOM 2525 N ILE A 321 −0.744 −67.396 8.209 1.00 119.23 A N ATOM 2526 CA ILE A 321 −0.449 −68.803 7.907 1.00 120.07 A C ATOM 2527 CB ILE A 321 −1.437 −69.445 6.878 1.00 120.16 A C ATOM 2528 CG1 ILE A 321 −2.720 −68.616 6.664 1.00 120.48 A C ATOM 2529 CD1 ILE A 321 −3.766 −68.700 7.770 1.00 121.91 A C ATOM 2530 CG2 ILE A 321 −1.693 −70.910 7.222 1.00 120.46 A C ATOM 2531 C ILE A 321 0.947 −68.920 7.302 1.00 120.58 A C ATOM 2532 O ILE A 321 1.645 −69.915 7.508 1.00 120.51 A O ATOM 2533 N LEU A 322 1.331 −67.894 6.541 1.00 121.34 A N ATOM 2534 CA LEU A 322 2.644 −67.826 5.928 1.00 121.99 A C ATOM 2535 CB LEU A 322 2.710 −66.707 4.879 1.00 121.91 A C ATOM 2536 CG LEU A 322 3.762 −66.808 3.759 1.00 122.11 A C ATOM 2537 CD1 LEU A 322 3.486 −67.954 2.783 1.00 121.91 A C ATOM 2538 CD2 LEU A 322 3.862 −65.496 2.996 1.00 122.27 A C ATOM 2539 C LEU A 322 3.681 −67.631 7.019 1.00 122.48 A C ATOM 2540 O LEU A 322 4.559 −68.479 7.183 1.00 122.74 A O ATOM 2541 N GLU A 323 3.553 −66.539 7.779 1.00 123.00 A N ATOM 2542 CA GLU A 323 4.439 −66.246 8.911 1.00 123.57 A C ATOM 2543 CB GLU A 323 3.881 −65.101 9.755 1.00 123.45 A C ATOM 2544 CG GLU A 323 3.922 −63.730 9.105 1.00 123.81 A C ATOM 2545 CD GLU A 323 2.964 −62.733 9.764 1.00 124.47 A C ATOM 2546 OE1 GLU A 323 2.298 −63.110 10.755 1.00 124.88 A O ATOM 2547 OE2 GLU A 323 2.872 −61.575 9.287 1.00 124.20 A O ATOM 2548 C GLU A 323 4.649 −67.471 9.805 1.00 124.12 A C ATOM 2549 O GLU A 323 5.779 −67.772 10.197 1.00 124.30 A O ATOM 2550 N ASN A 324 3.565 −68.179 10.116 1.00 124.70 A N ATOM 2551 CA ASN A 324 3.633 −69.325 11.013 1.00 125.45 A C ATOM 2552 CB ASN A 324 2.237 −69.888 11.322 1.00 125.32 A C ATOM 2553 CG ASN A 324 1.278 −68.832 11.876 1.00 125.29 A C ATOM 2554 OD1 ASN A 324 1.680 −67.915 12.594 1.00 124.69 A O ATOM 2555 ND2 ASN A 324 −0.002 −68.960 11.533 1.00 125.22 A N ATOM 2556 C ASN A 324 4.559 −70.412 10.480 1.00 126.21 A C ATOM 2557 O ASN A 324 5.469 −70.840 11.186 1.00 126.38 A O ATOM 2558 N TYR A 325 4.344 −70.830 9.231 1.00 127.20 A N ATOM 2559 CA TYR A 325 5.127 −71.914 8.610 1.00 128.15 A C ATOM 2560 CB TYR A 325 4.484 −72.378 7.295 1.00 128.33 A C ATOM 2561 CG TYR A 325 5.371 −73.236 6.400 1.00 128.28 A C ATOM 2562 CD1 TYR A 325 5.385 −74.623 6.517 1.00 128.19 A C ATOM 2563 CE1 TYR A 325 6.196 −75.403 5.693 1.00 128.69 A C ATOM 2564 CZ TYR A 325 7.001 −74.791 4.740 1.00 128.32 A C ATOM 2565 OH TYR A 325 7.809 −75.546 3.918 1.00 128.32 A O ATOM 2566 CE2 TYR A 325 6.998 −73.419 4.607 1.00 128.03 A C ATOM 2567 CD2 TYR A 325 6.182 −72.652 5.426 1.00 128.22 A C ATOM 2568 C TYR A 325 6.581 −71.548 8.366 1.00 128.78 A C ATOM 2569 O TYR A 325 7.457 −72.405 8.457 1.00 128.84 A O ATOM 2570 N PHE A 326 6.831 −70.288 8.026 1.00 129.74 A N ATOM 2571 CA PHE A 326 8.196 −69.807 7.856 1.00 130.77 A C ATOM 2572 CB PHE A 326 8.226 −68.477 7.104 1.00 130.66 A C ATOM 2573 CG PHE A 326 8.498 −68.634 5.633 1.00 131.15 A C ATOM 2574 CD1 PHE A 326 9.279 −67.709 4.954 1.00 131.45 A C ATOM 2575 CE1 PHE A 326 9.534 −67.857 3.595 1.00 131.35 A C ATOM 2576 CZ PHE A 326 9.022 −68.953 2.905 1.00 131.18 A C ATOM 2577 CE2 PHE A 326 8.254 −69.894 3.574 1.00 130.77 A C ATOM 2578 CD2 PHE A 326 7.999 −69.733 4.930 1.00 131.24 A C ATOM 2579 C PHE A 326 8.936 −69.738 9.184 1.00 131.50 A C ATOM 2580 O PHE A 326 10.052 −70.254 9.305 1.00 131.64 A O ATOM 2581 N SER A 327 8.299 −69.136 10.184 1.00 132.39 A N ATOM 2582 CA SER A 327 8.799 −69.202 11.551 1.00 133.35 A C ATOM 2583 CB SER A 327 8.346 −67.976 12.343 1.00 133.34 A C ATOM 2584 OG SER A 327 8.873 −66.797 11.762 1.00 133.24 A O ATOM 2585 C SER A 327 8.380 −70.520 12.228 1.00 133.99 A C ATOM 2586 O SER A 327 7.698 −70.524 13.255 1.00 134.15 A O ATOM 2587 N SER A 328 8.785 −71.633 11.618 1.00 134.76 A N ATOM 2588 CA SER A 328 8.560 −72.981 12.142 1.00 135.55 A C ATOM 2589 CB SER A 328 7.116 −73.442 11.917 1.00 135.43 A C ATOM 2590 OG SER A 328 6.926 −73.939 10.604 1.00 135.43 A O ATOM 2591 C SER A 328 9.540 −73.957 11.491 1.00 136.19 A C ATOM 2592 O SER A 328 9.619 −75.124 11.875 1.00 136.23 A O ATOM 2593 N LEU A 329 10.272 −73.471 10.491 1.00 137.16 A N ATOM 2594 CA LEU A 329 11.387 −74.218 9.910 1.00 138.16 A C ATOM 2595 CB LEU A 329 11.407 −74.077 8.381 1.00 138.39 A C ATOM 2596 CG LEU A 329 11.338 −75.401 7.597 1.00 138.89 A C ATOM 2597 CD1 LEU A 329 10.528 −75.238 6.308 1.00 138.84 A C ATOM 2598 CD2 LEU A 329 12.729 −76.000 7.323 1.00 139.11 A C ATOM 2599 C LEU A 329 12.693 −73.730 10.560 1.00 138.51 A C ATOM 2600 O LEU A 329 13.787 −74.236 10.275 1.00 138.46 A O ATOM 2601 N LYS A 330 12.536 −72.734 11.437 1.00 138.95 A N ATOM 2602 CA LYS A 330 13.549 −72.310 12.400 1.00 139.20 A C ATOM 2603 CB LYS A 330 13.455 −70.800 12.619 1.00 139.08 A C ATOM 2604 CG LYS A 330 13.404 −70.002 11.320 1.00 138.84 A C ATOM 2605 CD LYS A 330 12.923 −68.572 11.529 1.00 138.54 A C ATOM 2606 CE LYS A 330 14.069 −67.633 11.857 1.00 138.22 A C ATOM 2607 NZ LYS A 330 13.684 −66.229 11.575 1.00 138.27 A N ATOM 2608 C LYS A 330 13.339 −73.060 13.725 1.00 139.55 A C ATOM 2609 O LYS A 330 14.168 −72.985 14.632 1.00 139.50 A O ATOM 2610 N ASN A 331 12.214 −73.775 13.813 1.00 140.04 A N ATOM 2611 CA ASN A 331 11.873 −74.659 14.934 1.00 140.56 A C ATOM 2612 CB ASN A 331 10.355 −74.606 15.173 1.00 140.51 A C ATOM 2613 CG ASN A 331 9.949 −75.079 16.562 1.00 140.17 A C ATOM 2614 OD1 ASN A 331 9.623 −74.265 17.426 1.00 139.91 A O ATOM 2615 ND2 ASN A 331 9.950 −76.393 16.776 1.00 139.41 A N ATOM 2616 C ASN A 331 12.314 −76.110 14.639 1.00 140.98 A C ATOM 2617 O ASN A 331 12.161 −76.568 13.501 1.00 141.01 A O ATOM 2618 N PRO A 332 12.871 −76.827 15.653 1.00 141.35 A N ATOM 2619 CA PRO A 332 13.332 −78.222 15.545 1.00 141.44 A C ATOM 2620 CB PRO A 332 13.057 −78.776 16.949 1.00 141.46 A C ATOM 2621 CG PRO A 332 13.186 −77.556 17.868 1.00 141.67 A C ATOM 2622 CD PRO A 332 13.182 −76.301 16.997 1.00 141.45 A C ATOM 2623 C PRO A 332 12.616 −79.072 14.493 1.00 141.44 A C ATOM 2625 OXT PRO A 332 13.215 −79.439 13.481 1.00 141.35 A O ATOM 2626 NAV DRG B 1 −23.713 −62.247 −7.614 1.00 77.69 N ATOM 2627 CBB DRG B 1 −23.360 −63.208 −6.766 1.00 78.09 C ATOM 2628 CAK DRG B 1 −22.301 −63.335 −5.875 1.00 75.97 C ATOM 2629 CAI DRG B 1 −22.187 −64.483 −5.099 1.00 74.06 C ATOM 2630 CAZ DRG B 1 −23.130 −65.498 −5.214 1.00 75.54 C ATOM 2631 CBO DRG B 1 −23.003 −66.759 −4.359 1.00 75.85 C ATOM 2632 CAD DRG B 1 −21.560 −67.259 −4.429 1.00 75.72 C ATOM 2633 CAE DRG B 1 −23.382 −66.419 −2.918 1.00 77.20 C ATOM 2634 CAC DRG B 1 −23.955 −67.819 −4.918 1.00 74.37 C ATOM 2635 CAM DRG B 1 −24.188 −65.368 −6.106 1.00 77.60 C ATOM 2636 CBC DRG B 1 −24.300 −64.220 −6.881 1.00 78.94 C ATOM 2637 NAW DRG B 1 −25.184 −63.832 −7.794 1.00 78.28 N ATOM 2638 CBA DRG B 1 −24.826 −62.628 −8.241 1.00 79.13 C ATOM 2639 CAN DRG B 1 −25.571 −61.816 −9.301 1.00 79.81 C ATOM 2640 CAO DRG B 1 −24.986 −62.063 −10.693 1.00 79.86 C ATOM 2641 CBG DRG B 1 −25.614 −63.300 −11.340 1.00 80.40 C ATOM 2642 CAQ DRG B 1 −24.819 −64.545 −10.941 1.00 78.89 C ATOM 2643 CAP DRG B 1 −25.105 −63.439 −12.776 1.00 79.82 C ATOM 2644 CBH DRG B 1 −24.419 −64.755 −12.403 1.00 78.01 C ATOM 2645 NBM DRG B 1 −22.964 −64.605 −12.540 1.00 75.33 N ATOM 2646 CBF DRG B 1 −22.289 −65.703 −11.833 1.00 73.44 C ATOM 2647 CAB DRG B 1 −22.500 −67.011 −12.599 1.00 71.28 C ATOM 2648 CAA DRG B 1 −20.799 −65.383 −11.695 1.00 73.40 C ATOM 2649 CAR DRG B 1 −22.599 −64.642 −13.964 1.00 70.65 C ATOM 2650 CBK DRG B 1 −22.016 −63.289 −14.377 1.00 65.92 C ATOM 2651 OAX DRG B 1 −20.589 −63.395 −14.485 1.00 64.75 O ATOM 2652 CBI DRG B 1 −22.471 −62.950 −15.798 1.00 64.30 C ATOM 2653 OAG DRG B 1 −23.564 −62.031 −15.743 1.00 65.97 O ATOM 2654 CBJ DRG B 1 −21.254 −62.261 −16.418 1.00 63.34 C ATOM 2655 OAH DRG B 1 −21.588 −60.911 −16.750 1.00 64.58 O ATOM 2656 CBL DRG B 1 −20.216 −62.269 −15.294 1.00 58.52 C ATOM 2657 N9 DRG B 1 −18.870 −62.496 −15.866 1.00 51.11 N ATOM 2658 C8 DRG B 1 −18.311 −63.682 −16.109 1.00 51.98 C ATOM 2659 N7 DRG B 1 −17.095 −63.499 −16.624 1.00 46.56 N ATOM 2660 C5 DRG B 1 −16.880 −62.191 −16.710 1.00 39.50 C ATOM 2661 C4 DRG B 1 −18.007 −61.552 −16.229 1.00 41.15 C ATOM 2662 N3 DRG B 1 −18.045 −60.213 −16.207 1.00 40.98 N ATOM 2663 C2 DRG B 1 −17.014 −59.506 −16.641 1.00 44.16 C ATOM 2664 N1 DRG B 1 −15.919 −60.086 −17.109 1.00 40.65 N ATOM 2665 C6 DRG B 1 −15.818 −61.421 −17.158 1.00 39.87 C ATOM 2666 N6 DRG B 1 −14.715 −61.999 −17.628 1.00 45.08 N END 

1. A compound of Formula (I) below or a pharmaceutically acceptable salt or ester thereof:

wherein, Nuc is adenosine-like moiety or an analog or a derivative thereof, T is a linker group of a 6-10 carbon atoms, in which one or more carbon atoms are optionally replaced with a heteroatom and T is optionally substituted; Nuc-T is capable of binding within the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO: 1; and R₉ is a group such that R₉ induces a conformational adaptation in human DOT1L, wherein the conformational adaptation is the formation of a hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO:
 1. 2. The compound of claim 1 wherein the R₉ is a group such that R₉ induces a residence time of the compound greater than 20 seconds in a complex formed of the compound and human DOT1L.
 3. The compound of claim 1, wherein the SAM binding pocket of human DOT1L is characterized by the crystallography coordinates of one or more human DOT1L amino acids Val135, Thr139, Asp161, Gly163, Gln168, Glu 186, Asp222, Phe223, and Asn241, according to Table S1 or S2.
 4. The compound of claim 1, wherein the hydrophobic pocket domain of human DOT L is characterized by the crystallography coordinates of human DOT L amino acids Leu143, Met147, Phe239, and Tyr312, according to Table S1 or S2.
 5. The compound of claim 1, wherein the binding affinity (K_(i)) of the compound to human DOT1L is not greater than 50 μM.
 6. The compound of claim 1, wherein R₉ comprises C₆-C₁₀ aryl or 5 to 10-membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of unsubstituted or substituted t-butyl, CF₃, cyclohexyl, C₆-C₁₀ aryl, and 5 to 10-membered heteroaryl.
 7. The compound of claim 6, wherein the one or more substituents are t-butyl.
 8. The compound of claim 6, wherein R₉ is selected from the group consisting of


9. The compound of claim 1, being of formula (II):

wherein, A is O or CH₂; each of G and J, independently, is H, halo, C(O)OH, C(O)O—C₁-C₆ alkyl or OR_(a), R_(a) being H, C₁-C₆ alkyl, C(O)—C₁-C₆ alkyl, or silyl, wherein C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃—C cycloalkyl; each X independently is N or CR_(x), in which R_(x) is H, halo, hydroxyl, carboxyl, cyano, or R_(S1), R_(S1) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(S1) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃—C cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; each of R₁ and R₂, independently is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₈ cycloalkyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃—C cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; R₈ is H, halo or R_(S3), R_(S3) being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and R_(S3) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C₁-C₆ alkoxyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and C₃-C₈ cycloalkyl; and Q is H, NH₂, NHR_(b), NR_(b)R_(c), R_(b), ═O, OH, or OR_(b), in which each of R_(b) and R_(c) independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M₁-T₁ in which M₁ is a bond or C₁-C₆ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxyl and T₁ is C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R_(b) and R_(c), together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R_(b), R_(c), and T₁ is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl.
 10. The compound of claim 9, wherein T is —CH₂-L₁-L₂-L₃-, with L₃ connected to R₉, wherein: L₁ is N(Y), S, SO, or SO₂; L₂ is CO or absent when L₁ is N(Y), or L₂ is absent when L₁ is S, SO, or SO₂, in which Y is H, R_(d), SO₂R_(d), or COR_(d) when L₂ is absent, or Y is H or R_(d) when L₂ is CO, R_(d) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R_(d) being optionally substituted with one or more substituents selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, carboxyl, cyano, C₁-C₆ alkoxyl, C₁-C₆ alkylsulfonyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, OR_(d′), OCOR_(d′), and N(R_(d′))₂, and with C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C₁-C₆ alkyl, OC(O)—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl; each R_(d′) independently being H, C₁-C₆ alkyl, silyl, C₁-C₆ alkyl-C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 5 to 6-membered heteroaryl, aralkyl, or heteroaralkyl; L₃ is —(CR₄R₅)_(n)(CR₆R₇)_(m)— or —(CR₄R₅)_(n)-unsubstituted or substituted C₃-C₈ cycloalkyl-(CR₆R₇)_(m)—, with (CR₆R₇)_(m) connected to R₉; each of R₄, R₅, R₆, and R₇, independently, is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), R_(S2) being amino, C₁-C₆ alkoxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, and each R_(S2) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; or two geminal R₄ and R₅ or two geminal R₆ and R₇ taken together are ethylene, propylene or butylene; m is 0, 1, or 2; and n is 0, 1, or
 2. 11. The compound of claim 9, wherein R₉ is

in which: each of R_(e), R_(f), R_(g), and R_(h), independently is -M₂-T₂, in which M₂ is a bond, SO₂, SO, S, CO, CO₂, O, O—C—C₄ alkyl linker, C₁-C₄ alkyl linker, NH, or N(R_(t)), R_(t) being C₁-C₆ alkyl, and T₂ is H, halo, or R_(S4), R_(S4) being C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C₁-C₄ alkyl linker, C₁-C₄ alkyl linker, R_(t), and R_(S4) being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R_(i) is H or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR_(j), or CR_(j)R_(k), each of R_(j) and R_(k) independently being H or C₁-C₆ alkyl, or R_(j) and R_(k) taken together, with the carbon atom to which they are attached, form a C₃-C₁₀ cycloalkyl ring, and E is -M₃-T₃, M₃ being a bond or C₁-C₆ alkyl linker optionally substituted with halo or cyano, T₃ being C₃-C₁₄ carbocycle or 4 to 14-membered heterocycle, and T₃ being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, oxo, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₄-C₁₂ alkylcycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryloxyl, C₇-C₁₄ alkylaryl, C₆-C₁₀ aminoaryloxyl, C₆-C₁₀ arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C₁-C₄ alkyl, and C₁-C₆ alkyl that is substituted with hydroxy, halo, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C₁-C₆ alkoxyl.
 12. The compound of claim 10, wherein the compound is of formula (IIIa) or (IIIb):

wherein R₃ is H, halo, hydroxyl, carboxyl, cyano, or R_(S2), and q is 0, 1, 2, 3, or
 4. 13. The compound of claim 12, wherein the compound is of formula (IIIa) and R₉ is

or the compound is of formula (IIIb) and R₉ is


14. (canceled)
 15. A method for the design and identification of a potential binding compound for protein DOT1L comprising the steps of: (a) generating, on a computer, a three-dimensional structure of DOT1L having the structural coordinates of Table S1 or S2; (b) identifying amino acid residues forming an hydrophobic pocket site in the three-dimensional structure of DOT1L from step (a), wherein the hydrophobic pocket domain of DOT1L is characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr312 according to Table S1 or S2; (c) generating a three-dimensional model of the active site; (d) designing and/or selecting a compound that potentially binds to the active site using the three-dimensional model of the active site; and (e) synthesizing and/or choosing the potential binding compound. 16-18. (canceled)
 19. A DOT1L inhibitor having molecular dimensions compatible with the shape of a hydrophobic pocket domain of DOT1L characterized by the crystallography coordinates of human DOT1L amino acids Leu143, Met147, Phe239, and Tyr312, according to Table S1 or S2, wherein the compound has a biochemical IC₅₀ for DOT1L of less than 100 nM. 20-22. (canceled)
 23. A method for designing, identifying, and/or optimizing a candidate DOT1L inhibitor compound or complex, the method comprising: (a) generating a crystal structure, a three-dimensional model of DOT1L, or obtaining the structure coordinates of DOT1L in complex with the candidate DOT1L inhibitor compound or complex, and (b) determining if the candidate DOT L inhibitor compound or complex induces a conformational adaptation and/or a hydrophobic binding site of the DOT1L from the three-dimensional model.
 24. The method of claim 23, further comprising contacting the identified candidate inhibitor with DOT1L in order to determine the effect of the inhibitor on DOT1L enzymatic activity.
 25. (canceled)
 26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a DOT1L inhibitor designed, identified, and/or optimized by the method of claim
 15. 28. A method for treating cancer comprising administrating a therapeutically effective amount of a compound of claim 1 to a subject in need thereof. 29-32. (canceled) 